Oral composition of celecoxib for treatment of pain

ABSTRACT

The present invention relates to a stable oral liquid pharmaceutical composition of celecoxib or its pharmaceutically acceptable salts thereof. The celecoxib present in the compositions as described herein do not show any precipitation when subjected in Fasted-State Simulated Gastric Fluid (FaSSGF) at pH 2.0, temperature of 37° C.±0.5° C. and under stirring at a speed of 50 rpm at least for 60 minutes. It also relates to the process of preparing and method of using said composition of celecoxib.

PRIORITY

This application claims priority to Indian Patent Application Nos.2682/CHE/2015, filed May 28, 2015, and 6614/CHE/2015, filed Dec. 10,2015, the entire disclosures of which are incorporated herein byreference in their entireties.

BACKGROUND

Non-steroidal anti-inflammatory drugs (NSAID) are generally used for thetreatment of acute pain, inflammatory pain, visceral pain, breakthroughpain, nociceptive pain, neuropathic pain, dysmenorrhea, post-surgicalpain, acute postpartum pain, postoperative pain management chronic painin osteoarthritis, rheumatoid arthritis and pain due to other diseasesand causes.

Celecoxib is approved in U.S. under brand name CELEBREX®, as oralcapsules and used in the treatment of osteoarthritis, rheumatoidarthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acutepain, chronic pain, primary dysmenorrhea and familial adenomatouspolyposis. It is available in the strengths of 50 mg, 100 mg, 200 mg and400 mg.

Celecoxib was described in U.S. Pat. No. 5,466,823 assigned to Searle, aclass of 1, 5-diaryl pyrazoles and their salts together with processesfor the preparation of such compounds.

Celecoxib is chemically designated as4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide and is a diaryl-substituted pyrazole. The empiricalformula is C₁₇H₁₄F₃N₃O₂S, and the molecular weight is 381.38; thechemical structure is as follows:

U.S. Pat. No. 5,466,823 contains general references to formulations forthe administration of 1,5-diaryl pyrazoles, including orally deliverabledosage forms such as tablets and capsules.

U.S. Pat. No. 5,760,068 describes a class of 1,5-diaryl pyrazolecompounds including celecoxib that are selective inhibitors ofcyclooxygenase-2 and can be administered to treat, among otherconditions and disorders, pathological conditions associated withrheumatoid arthritis and osteoarthritis.

Celecoxib is a hydrophobic and highly permeable drug belonging to classII of biopharmaceutics classification system. Celecoxib is a neutralmolecule that is essentially insoluble in water which leads to highvariability in absorption and hence has limited bioavailability afteroral administration. It also has pre-systemic metabolism.

Celecoxib has an aqueous solubility of about 5 μg/ml at between 5° C.and 40° C., which is pH independent at pH<9. Celecoxib is not readilydissolved and dispersed for rapid absorption in the gastrointestinaltract when administered orally, for example in capsule form. Oraladministration is associated with a delayed onset of the desiredpharmacological action. It is known that upon oral administration,celecoxib takes approximately 3.0 hours for peak plasma concentrationsto be achieved and hence have delayed onset of action afteradministration. Additionally, the intake of food further influences drugabsorption. However, acute pains, as in the case of migraine pain,surgical pain, trauma, pain due to kidney stones, and arthritis, demandimmediate/faster pain relief.

Accordingly, there is a long felt need to develop a composition forcelecoxib or its pharmaceutical salts thereof, which can be readilydissolved/dispersed for rapid absorption in the gastrointestinal tractin order to provide faster pain relief

SUMMARY

Some embodiments disclosed herein provide stable oral liquidpharmaceutical compositions, comprising a therapeutically effectiveamount of celecoxib, at least one solubiliser, at least one medium chainglyceride, at least one polar solvent, and at least one pharmaceuticallyacceptable excipient, wherein said composition does not show anyprecipitation in Fasted-State Simulated Gastric Fluid (FaSSGF) at pH of2.0, temperature of 37° C.±0.5° C. and under stirring at a speed of 50rpm, when measured at 60 min. In some embodiments, the composition isessentially free of precipitation inhibitors selected from the groupconsisting of polyvinyl caprolactam-polyvinyl acetate-polyethyleneglycol graft copolymer (SOLUPLUS®), polyoxyethylene-polyoxypropyleneblock copolymers, pluronics, polyvinylpyrrolidone, and cellulosicpolymers, including hydroxypropyl cellulose and hydroxypropylmethylcellulose. In some embodiments, the at least one solubiliser ispolyethoxylated castor oil (available as KOLLIPHOR EL®), laurylmacrogolglyceride (available as GELUCIRE® 44/14), or a combinationthereof. In some embodiments, the at least one medium chain glyceride isglyceryl tricaprylate/tricaprate (available as CAPTEX® 300), glycerylmonocaprylate (available as CAPMUL® MCM C8), or a combination thereof.In some embodiments, the at least one polar solvent is selected from thegroup consisting of propylene glycol, polyethylene glycols having amolecular weight between 400 and 1000, glycerin, C2 to C8 mono- andpoly-alcohols (e.g., ethanol), C7 to C18 alcohols of linear or branchedconfiguration, water and mixtures thereof. In some embodiments, thetherapeutically effective amount of celecoxib comprises from about 1% toabout 80% celecoxib by weight, based on the total weight of thecomposition. In some embodiments, the at least one solubiliser ispresent in an amount of from about 10% to about 70% by weight, based onthe total weight of the composition. In some embodiments, a weight ratioof the at least one solubiliser to celecoxib varies from about 4.0:1.0to about 20:1.0. In some embodiments, the at least one polar solvent ispresent in an amount of from about 20% to about 80% by weight, based onthe total weight of the composition. In some embodiments, a weight ratioof the at least one solubiliser to the at least one polar solvent variesfrom about 0.60:1.00 to about 1.8:1.00. In some embodiments, the atleast one medium chain glyceride is present in an amount of from about5% to about 75% by weight, based on the total weight of the composition.In some embodiments, the composition has a mean oil droplet size of notmore than 500 nm, when tested in 250 ml of Fasted-State SimulatedGastric Fluid (FaSSGF) at pH of 2.0, temperature of 37° C.±0.5° C. andunder stirring at a speed of 50 rpm. In some embodiments, thecomposition has a viscosity of from about 20 cps to about 1000 cps. Insome embodiments, the composition has a density of from about 0.8 gm/cm³to about 2 gm/cm³. In some embodiments, the composition has atransmittance of at least 40%. In some embodiments, the composition hasa pH of from about 3 to about 7. In some embodiments, thetherapeutically effect amount of celecoxib is at least about 40% lessthan conventional celecoxib compositions such as CELEBREX® 400 mg oralcapsules. In some embodiments, the therapeutically effect amount ofcelecoxib is about 240 mg. In some embodiments, the therapeuticallyeffect amount of celecoxib is at least about 55% less than conventionalcelecoxib compositions such as CELEBREX® 400 mg oral capsules. In someembodiments, the therapeutically effect amount of celecoxib is about 180mg. In some embodiments, the therapeutically effect amount of celecoxibis at least about 70% less than conventional celecoxib compositions suchas CELEBREX® 400 mg oral capsules. In some embodiments, thetherapeutically effect amount of celecoxib is about 120 mg. In someembodiments, the stable oral liquid pharmaceutical compositions, whichupon oral administration to a human subject under fasting conditions,provides at least one of the following pharmacokinetic parameters:

AUC_((0-15min)) from about 10 ng·h/mL to about 80 ng·h/mL;

AUC_((0-30min)) from about 80 ng·h/mL to about 400 ng·h/mL;

AUC_((0-1hr)) from about 400 ng·h/mL to about 1500 ng·h/mL;

AUC_((0-2hr)) from about 1000 ng·h/mL to about 4000 ng·h/mL;

AUC_((0-t)) of at least about 2000 ng·h/mL;

AUC_((0-∞)) of at least about 2000 ng·h/mL; and

T_(lag) of not more than 8 minutes.

In some embodiments, the stable oral liquid pharmaceutical compositionscomprise: a) a therapeutically effective amount of celecoxib; b) atleast one pharmaceutically acceptable excipient; c) at least onesolubiliser in an amount from about 35% w/w to about 45% w/w; and d) atleast one polar solvent in an amount from about 25% w/w to about 42%w/w, wherein the solubiliser and polar solvent are present in a ratio offrom about 0.60:1 to about 1.8:1; and wherein the stable oral liquidpharmaceutical composition has a viscosity of from about 20 cps to about1000 cps, and a density of from about 0.8 gm/cm³ to about 2 gm/cm³.

Some embodiments disclosed here provide stable oral liquidpharmaceutical compositions comprising from about 100 mg to 250 mg ofcelecoxib, at least one pharmaceutically acceptable excipient, at leastone solubiliser, at least one medium chain glyceride, and at least onepolar solvent, wherein the composition: a) releases no less than about70% of the celecoxib at a period of 10 minutes; or b) releases no lessthan about 80% of the celecoxib at a period of 15 minutes, in 900 ml of0.01N HCl with 0.5% sodium lauryl sulfate, when tested in a USP Type 2apparatus with sinkers at 50 rpm and 37° C. In some embodiments, thecomposition is essentially free of precipitation inhibitors selectedfrom the group consisting of polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (SOLUPLUS®),polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, and cellulosic polymers, including hydroxypropylcellulose and hydroxypropyl methylcellulose. In some embodiments, the atleast one solubiliser is polyethoxylated castor oil (available asKOLLIPHOR EL®), lauryl macrogolglyceride (available as GELUCIRE® 44/14),or a combination thereof. In some embodiments, the at least one mediumchain glyceride is glyceryl tricaprylate/tricaprate (available asCAPTEX® 300), glyceryl monocaprylate (available as CAPMUL® MCM C8), or acombination thereof. In some embodiments, the at least one polar solventis selected from the group consisting of propylene glycol, polyethyleneglycols having a molecular weight between 400 and 1000, glycerin, C2 toC8 mono- and poly-alcohols (e.g., ethanol), C7 to C18 alcohols of linearor branched configuration, water and mixtures thereof. In someembodiments, the therapeutically effective amount of celecoxib comprisesfrom about 1% to about 80% celecoxib by weight, based on the totalweight of the composition. In some embodiments, the at least onesolubiliser is present in an amount of from about 10% to about 70% byweight, based on the total weight of the composition. In someembodiments, a weight ratio of the at least one solubiliser to celecoxibvaries from about 4.0:1.0 to about 20:1.0. In some embodiments, the atleast one polar solvent is present in an amount of from about 20% toabout 80% by weight, based on the total weight of the composition. Insome embodiments, a weight ratio of the at least one solubiliser to theat least one polar solvent varies from about 0.60:1.00 to about1.8:1.00. In some embodiments, the at least one medium chain glycerideis present in an amount of from about 5% to about 75% by weight, basedon the total weight of the composition. In some embodiments, thecomposition has a mean oil droplet size of not more than 500 nm, whentested in 250 ml of Fasted-State Simulated Gastric Fluid (FaSSGF) at pHof 2.0, temperature of 37° C.±0.5° C. and under stirring at a speed of50 rpm. In some embodiments, the composition has a viscosity of fromabout 20 cps to about 1000 cps. In some embodiments, the composition hasa density of from about 0.8 gm/cm³ to about 2 gm/cm³. In someembodiments, the composition has a transmittance of at least 40%. Insome embodiments, the composition has a pH of from about 3 to about 7.In some embodiments, the therapeutically effect amount of celecoxib isat least about 40% less than conventional celecoxib compositions such asCELEBREX® 400 mg oral capsules. In some embodiments, the therapeuticallyeffect amount of celecoxib is about 240 mg. In some embodiments, thetherapeutically effect amount of celecoxib is at least about 55% lessthan conventional celecoxib compositions such as CELEBREX® 400 mg oralcapsules. In some embodiments, the therapeutically effect amount ofcelecoxib is about 180 mg. In some embodiments, the therapeuticallyeffect amount of celecoxib is at least about 70% less than conventionalcelecoxib compositions such as CELEBREX® 400 mg oral capsules. In someembodiments, the therapeutically effect amount of celecoxib is about 120mg. In some embodiments, the stable oral liquid pharmaceuticalcompositions, which upon oral administration to a human subject underfasting conditions, provides at least one of the followingpharmacokinetic parameters:

AUC_((0-15min)) from about 10 ng·h/mL to about 80 ng·h/mL;

AUC_((0-30min)) from about 80 ng·h/mL to about 400 ng·h/mL;

AUC_((0-1hr)) from about 400 ng·h/mL to about 1500 ng·h/mL;

AUC_((0-2hr)) from about 1000 ng·h/mL to about 4000 ng·h/mL;

AUC_((0-t)) of at least about 2000 ng·h/mL;

AUC_((0-∞)) of at least about 2000 ng·h/mL; and

T_(lag) of not more than 8 minutes.

In some embodiments, the stable oral liquid pharmaceutical compositionscomprise: a) a therapeutically effective amount of celecoxib; b) atleast one pharmaceutically acceptable excipient; c) at least onesolubiliser in an amount from about 35% w/w to about 45% w/w; and d) atleast one polar solvent in an amount from about 25% w/w to about 42%w/w, wherein the solubiliser and polar solvent are present in a ratio offrom about 0.60:1 to about 1.8:1; and wherein the stable oral liquidpharmaceutical composition has a viscosity of from about 20 cps to about1000 cps, and a density of from about 0.8 gm/cm³ to about 2 gm/cm³.

Some embodiments disclosed herein provide methods of treating pain in ahuman subject, the method comprising administering to the subject astable oral liquid pharmaceutical composition, comprising atherapeutically effective amount of celecoxib, at least one solubiliserin amount from about 35 w/w to about 45 w/w, at least one polar solventin amount from about 25 w/w to about 42% w/w, at least one medium chainglyceride, and at least one pharmaceutically acceptable excipient,wherein the stable oral liquid pharmaceutical composition is essentiallyfree of precipitation inhibitors. In some embodiments, the pain isassociated with migraine. In some embodiments, the therapeuticallyeffective amount of celecoxib is sufficient to render the subject painfree within 2 hours of administering the stable oral liquidpharmaceutical composition. In some embodiments, the therapeuticallyeffective amount of celecoxib is sufficient to lead to partial painrelief in the subject within 2 hours of administering the stable oralliquid pharmaceutical composition. In some embodiments, administeringthe stable oral liquid pharmaceutical composition leads to pain free at2 hours in at least 25% of the human subjects being treated. In someembodiments, administering the stable oral liquid pharmaceuticalcomposition leads to partial pain relief at 2 hours in at least 45% ofthe human subjects being treated. In some embodiments, administering thestable oral liquid pharmaceutical composition leads to an increase inthe percentage of human subjects being treated being pain free at 2hours that is at least 40% in comparison to the percentage of humansubjects being treated with a placebo. In some embodiments,administering the stable oral liquid pharmaceutical composition leads toan increase in the percentage of human subjects being treated beingpartially relieved of pain at 2 hours that is at least 10% in comparisonto the percentage of human subjects being treated with a placebo. Insome embodiments, administering the stable oral liquid pharmaceuticalcomposition leads to an increase in the percentage of human subjectsbeing treated being pain free at 2 hours that is at least 10% incomparison to the percentage of human subjects being treated with acommercially available migraine pain treatment, such as VIOXX 25 (25mg), VIOXX 50 (50 mg) and CAMBIA 50 (50 mg). In some embodiments,administering the stable oral liquid pharmaceutical composition leads toan increase in the percentage of human subjects being treated beingpartially relieved of pain at 2 hours that is at least 10% in comparisonto the percentage of human subjects being treated with a commerciallyavailable migraine pain treatment, such as VIOXX 25 (25 mg), VIOXX 50(50 mg) and CAMBIA 50 (50 mg).

Some embodiments disclosed herein provide uses of a stable oral liquidpharmaceutical composition disclosed in any of the embodimentsthroughout this application for the treatment of pain in a subject. Insome embodiments, the stable oral liquid pharmaceutical compositioncomprises a therapeutically effective amount of celecoxib, at least onesolubiliser in amount from about 35% w/w to about 45% w/w, at least onepolar solvent in amount from about 25% w/w to about 42% w/w, at leastone medium chain glyceride, and at least one pharmaceutically acceptableexcipient, wherein the stable oral liquid pharmaceutical composition isessentially free of precipitation inhibitors. In some embodiments, thepain is associated with migraine. In some embodiments, thetherapeutically effective amount of celecoxib is sufficient to renderthe subject pain free within 2 hours of administering the stable oralliquid pharmaceutical composition. In some embodiments, thetherapeutically effective amount of celecoxib is sufficient to lead topartial pain relief in the subject within 2 hours of administering thestable oral liquid pharmaceutical composition. In some embodiments,administering the stable oral liquid pharmaceutical composition leads topain free at 2 hours in at least 25% of the human subjects beingtreated. In some embodiments, administering the stable oral liquidpharmaceutical composition leads to partial pain relief at 2 hours in atleast 45% of the human subjects being treated. In some embodiments,administering the stable oral liquid pharmaceutical composition leads toan increase in the percentage of human subjects being treated being painfree at 2 hours that is at least 40% in comparison to the percentage ofhuman subjects being treated with a placebo. In some embodiments,administering the stable oral liquid pharmaceutical composition leads toan increase in the percentage of human subjects being treated beingpartially relieved of pain at 2 hours that is at least 10% in comparisonto the percentage of human subjects being treated with a placebo. Insome embodiments, administering the stable oral liquid pharmaceuticalcomposition leads to an increase in the percentage of human subjectsbeing treated being pain free at 2 hours that is at least 10% incomparison to the percentage of human subjects being treated with acommercially available migraine pain treatment, such as VIOXX 25 (25mg), VIOXX 50 (50 mg) and CAMBIA 50 (50 mg). In some embodiments,administering the stable oral liquid pharmaceutical composition leads toan increase in the percentage of human subjects being treated beingpartially relieved of pain at 2 hours that is at least 10% in comparisonto the percentage of human subjects being treated with a commerciallyavailable migraine pain treatment, such as VIOXX 25 (25 mg), VIOXX 50(50 mg) and CAMBIA 50 (50 mg).

Some embodiments disclosed herein provide stable oral liquidpharmaceutical compositions of celecoxib comprising i. therapeuticallyeffective amount of celecoxib, at least one solubiliser, at least onemedium chain glyceride; and ii. polar solvent comprising mixture ofethanol and glycerin; wherein the composition falls within the shadedregion of a phase diagram, as shown in FIG. 1, wherein boundaries of astable composition are defined by shaded region or the region betweenthe connecting lines between the six points (a, b, c, d, e and f),wherein the composition comprises about 1% to about 80% w/w celecoxiband correspond to a weight % ratio of base composition:ethanol:glycerinof 0.200:0.024:0.712 for a, 0.200:0.376:0.360 for b, 0.200:0.400:0.336for c, 0.536:0.400:0.000 for d, 0.900:0.036:0.00 for e, and0.900:0.00:0.036 for f. In some embodiments, said composition does notshow any precipitation in Fasted-State Simulated Gastric Fluid (FaSSGF)at pH of 2.0, temperature of 37° C.±0.5° C. and under stirring at aspeed of 50 rpm, when measured at 60 min. In some embodiments, thecomposition is essentially free of precipitation inhibitors selectedfrom the group consisting of polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (SOLUPLUS®),polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, and cellulosic polymers, including hydroxypropylcellulose and hydroxypropyl methylcellulose. In some embodiments, the atleast one solubiliser is polyethoxylated castor oil (available asKOLLIPHOR EL®), lauryl macrogolglyceride (available as GELUCIRE® 44/14),or a combination thereof. In some embodiments, the at least one mediumchain glyceride is glyceryl tricaprylate/tricaprate (available asCAPTEX® 300), glyceryl monocaprylate (available as CAPMUL® MCM C8), or acombination thereof. In some embodiments, the at least one polar solventis selected from the group consisting of propylene glycol, polyethyleneglycols having a molecular weight between 400 and 1000, glycerin, C2 toC8 mono- and poly-alcohols (e.g., ethanol), C7 to C18 alcohols of linearor branched configuration, water and mixtures thereof. In someembodiments, the therapeutically effective amount of celecoxib comprisesfrom about 1% to about 80% celecoxib by weight, based on the totalweight of the composition. In some embodiments, the at least onesolubiliser is present in an amount of from about 10% to about 70% byweight, based on the total weight of the composition. In someembodiments, a weight ratio of the at least one solubiliser to celecoxibvaries from about 4.0:1.0 to about 20:1.0. In some embodiments, the atleast one polar solvent is present in an amount of from about 20% toabout 80% by weight, based on the total weight of the composition. Insome embodiments, a weight ratio of the at least one solubiliser to theat least one polar solvent varies from about 0.60:1.00 to about1.8:1.00. In some embodiments, the at least one medium chain glycerideis present in an amount of from about 5% to about 75% by weight, basedon the total weight of the composition. In some embodiments, thecomposition has a mean oil droplet size of not more than 500 nm, whentested in 250 ml of Fasted-State Simulated Gastric Fluid (FaSSGF) at pHof 2.0, temperature of 37° C.±0.5° C. and under stirring at a speed of50 rpm. In some embodiments, the composition has a viscosity of fromabout 20 cps to about 1000 cps. In some embodiments, the composition hasa density of from about 0.8 gm/cm³ to about 2 gm/cm³. In someembodiments, the composition has a transmittance of at least 40%. Insome embodiments, the composition has a pH of from about 3 to about 7.In some embodiments, the therapeutically effect amount of celecoxib isat least about 40% less than conventional celecoxib compositions such asCELEBREX® 400 mg oral capsules. In some embodiments, the therapeuticallyeffect amount of celecoxib is about 240 mg. In some embodiments, thetherapeutically effect amount of celecoxib is at least about 55% lessthan conventional celecoxib compositions such as CELEBREX® 400 mg oralcapsules. In some embodiments, the therapeutically effect amount ofcelecoxib is about 180 mg. In some embodiments, the therapeuticallyeffect amount of celecoxib is at least about 70% less than conventionalcelecoxib compositions such as CELEBREX® 400 mg oral capsules. In someembodiments, the therapeutically effect amount of celecoxib is about 120mg. In some embodiments, the stable oral liquid pharmaceuticalcompositions, which upon oral administration to a human subject underfasting conditions, provides at least one of the followingpharmacokinetic parameters:

AUC_((0-15min)) from about 10 ng·h/mL to about 80 ng·h/mL;

AUC_((0-30min)) from about 80 ng·h/mL to about 400 ng·h/mL;

AUC_((0-1hr)) from about 400 ng·h/mL to about 1500 ng·h/mL;

AUC_((0-2hr)) from about 1000 ng·h/mL to about 4000 ng·h/mL;

AUC_((0-t)) of at least about 2000 ng·h/mL;

AUC_((0-∞)) of at least about 2000 ng·h/mL; and

T_(lag) of not more than 8 minutes.

In some embodiments, the stable oral liquid pharmaceutical compositionscomprise: a) a therapeutically effective amount of celecoxib; b) atleast one pharmaceutically acceptable excipient; c) at least onesolubiliser in an amount from about 35% w/w to about 45% w/w; and d) atleast one polar solvent in an amount from about 25% w/w to about 42%w/w, wherein the solubiliser and polar solvent are present in a ratio offrom about 0.60:1 to about 1.8:1; and wherein the stable oral liquidpharmaceutical composition has a viscosity of from about 20 cps to about1000 cps, and a density of from about 0.8 gm/cm³ to about 2 gm/cm³.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a ternary phase diagram. The shaded region is “stablecomposition region A” and is formed by connecting lines between points(a, b, c, d, e and f).

FIG. 2 shows a ternary phase diagram. The shaded region is “stablecomposition region B” and is formed by connecting lines between points(a, b, c, d, e and f).

FIG. 3 shows a ternary phase diagram. The shaded region is “stablecomposition region C” and is formed by connecting lines between points(a, b, c, d, e, f, g and h).

FIG. 4 shows pain free in percentage of human subjects at 2 hoursresults of the Example 3 having 120 mg Celecoxib (Treatment-1) comparedto VIOXX 25, VIOXX 50 & CAMBIA 50.

FIG. 5 shows percentage pain relief in percentage of human subjects at 2hours results of the Example 3 having 120 mg Celecoxib (Treatment-1)compared to VIOXX 25, VIOXX 50 & CAMBIA 50.

DETAILED DESCRIPTION Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art.

As used herein, “comprising” is “open ended” and means the elementsrecited, or their equivalent in structure or function, plus any otherelement or elements which are not recited. The terms “having” and“including” are also to be construed as open ended unless the contextsuggests otherwise. All the ranges recited herein include the endpoints,including those that recite a range “between” two values.

The terms “a” and “the” as used herein are understood to encompass theplural as well as the singular or otherwise clearly mentioned whereverneeded. For example, reference to “an excipient” includes reference toone or more of such excipients, and reference to “the carrier” includesreference to one or more of such carriers.

The terms such as ‘about’, ‘up to’, ‘generally’, ‘substantially’ and thelike are to be construed as modifying a term or value such that it isnot an absolute. Such terms will be defined by the circumstances and theterms that they modify as those terms are understood by those of skilledin the art. This includes, at very least, the degree of expectedexperimental error, technical error and instrumental error for a givenexperiment, technique or an instrument used to measure a value. The term“about” is used to provide flexibility to a numerical range endpoint byproviding that a given value may be “a little above” or “a little below”the endpoint. As used herein, the term “about” means a slight variationof the value specified, preferably within 10% of the value specified.Nevertheless, the term “about” can mean a higher tolerance of variationdepending on for instance the experimental technique used. Saidvariations of a specified value are understood by the skilled person andare within the context of the present invention. As an illustration, anumerical range of “about 1 to about 5” should be interpreted to includenot only the explicitly recited values of about 1 to about 5, but alsoinclude individual values and sub-ranges within the indicated range.Thus, included in this numerical range are individual values such as 2,3, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc.,as well as 1, 2, 3, 4, 5, or 6, individually. This same principleapplies to ranges reciting only one numerical value as a minimum or amaximum.

As used herein, “free of” or “essentially free of” a particular compoundor compositions or excipients refer to the absence of any separatelyadded portion of the referenced compound or composition or excipients.The term “free of” or “essentially free of” means that there is lessthan 1% w/w of a particular compound or compositions, or excipients,wherein the amount present does not impart any functional value to thecomposition.

“Celecoxib” as used herein encompasses base form as well as itspharmaceutically acceptable salts, complexes, polymorphs, hydrates,solvates, enantiomers or racemates. The solid state form of celecoxibused in the composition of the present application is not critical. Forexample, celecoxib can be amorphous or crystalline.

The term “pharmaceutically acceptable salts” as used herein includesthose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like,which are well known in the art. The salts can be prepared in situduring the final isolation and purification of the compounds of theinvention, or separately by reacting the pharmaceutically activesubstance, having a freebase function, with a suitable organic acid orinorganic acid.

As used herein, an “effective amount” or a “therapeutically effectiveamount” of a drug refers to a non-toxic, but sufficient amount of thedrug, to achieve therapeutic results in treating a condition for whichthe drug is known to be effective. In this instance, an effective amountis an amount of celecoxib which is sufficient to treat pain in a patientin need thereof which is to say to provide some measure of analgesia toreduce at least the patient's perception of pain.

The term “liquid composition” refers to a liquid composition that isingested with or without further mixing with aqueous or suitable mediabefore oral administration.

The term “stable composition(s)” as used herein, refers to a compositionthat does not show any precipitation in Fasted-State Simulated GastricFluid (FaSSGF) at pH 2.0, temperature of 37° C.±0.5° C. and understirring at a speed of 50 rpm at least for 60 minutes. Also the term“stable composition(s)” refers to a composition which upon subjected tostability evaluation at 40° C. and 75% RH (relative humidity) or 25° C.and 60% RH (relative humidity), is substantially free of impurities, orcomprises not more than 5% impurities, or comprises impurities levelswhich are acceptable by regulatory bodies such as US FDA.

The term “precipitation inhibitor” as used herein refers to apharmaceutically acceptable excipient that prevents the precipitation ofcelecoxib when orally administered to a human subject, or when tested ina simulated gastric fluid, e.g., Fasted-State Simulated Gastric Fluid(FaSSGF), pH 2.0, at 37° C. under stirring condition. Examples ofprecipitation inhibitors include: polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (SOLUPLUS®),polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, and cellulosic polymers, including hydroxypropylcellulose and hydroxypropyl methylcellulose. Non-cellulosic polymersthat inhibit precipitation may also be included among the possibleprecipitation inhibitors.

The term “Fasted-State Simulated Gastric Fluid (FaSSGF)” as used herein,refers to a standard in vitro assay that is used to simulate theenvironment of the fasted-state gastric fluid for evaluation of thestability (or solubility or suitability) of drug formulations for oraldelivery. The composition of FaSSG is 0.1N HCl with 0.05% SLS and pHadjusted with NaOH/HCl.

The term “conventional celecoxib oral composition” or “conventionalcomposition” as used herein, refers to oral celecoxib capsules marketedunder the brand name CELEBREX® by G.D. Searle LLC in US or itspharmaceutical equivalents or its therapeutic equivalents or laterapproved drugs which are designated as AB rated by US FDA as perApproved Drug Products with Therapeutic Equivalence Evaluations (34thedition) or drugs obtained marketing approval by US FDA throughAbbreviated New Drug Application (ANDA) filing by establishingbioequivalence to such Product”. In some embodiments CELEBREX® includesits US FDA approved therapeutic or pharmaceutical equivalents. CELEBREX®is a Trademark registered and owned by G.D. Searle LLC (Division ofPfizer Inc. NY), NY 10017, USA. In some other embodiments “conventionalcelecoxib oral composition” or “conventional composition” also includesoral celecoxib capsules marketed under the brand name ZYCEL® by ZydusCadila, Zydus Tower, Ahmedabad, India. CELEBREX® is available in thestrengths of 50 mg, 100 mg, 200 mg and 400 mg celecoxib containing oralcapsules. ZYCEL® is available in the strengths of 100 mg and 200 mgcelecoxib containing oral capsules.

As used herein the term “pain” refers to pain as recited herein acutepain, migraine pain, cluster headache, neuropathic pain, post-operativepain, chronic lower back pain, herpes neuralgia, phantom limb pain,central pain, dental pain, neuropathic pain, opioid-resistant pain,visceral pain, surgical pain, bone injury pain, pain during labor anddelivery, pain resulting from burns, including sunburn, post-partumpain, angina pain, and genitourinary tract-related pain includingcystitis, arthritis pain, inflammation, osteoarthritis, juvenilerheumatoid arthritis, ankylosing spondylitis and primary dysmenorrhea.

As used herein the term “treating” includes treatment and/or prophylaxisof a physical and/or mental condition or amelioration or elimination ofthe developed condition once it has been established or alleviation ofthe characteristic symptoms of such condition.

As used herein, the term “mammal” shall refer to the mammalian class ofhigher vertebrates. The term “mammal” includes, but is not limited to, ahuman.

Stable Oral Liquid Pharmaceutical Compositions

In some embodiments, the present application provides stable oral liquidpharmaceutical compositions comprising a therapeutically effectiveamount of celecoxib. In some embodiments, the stable oral liquidpharmaceutical compositions disclosed herein comprise at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent, and/or at least one pharmaceutically acceptable excipient.

Without being bound by a particular theory, it is contemplated that thestable oral liquid pharmaceutical compositions disclosed herein showimproved solubilization characters, for example, when administeredorally to a human subject. In some embodiments, the stable oral liquidpharmaceutical compositions disclosed herein do not show anyprecipitation in a simulated gastric fluid (GSF) for a prolonged time.For example, the stable oral liquid pharmaceutical compositionsdisclosed herein do not show any precipitation in a simulated gastricfluid (GSF) for at least 10 min, at least 20 min, at least 30 min, atleast 40 min, at least 50 min, at least 60 min, at least 90 min, atleast 2 hr, at least 3 hr, at least 4 hr, at least 5 hr, at least 6 hr,at least 12 hr, at least 24 hr, or longer. In some embodiments, thestable oral liquid pharmaceutical compositions disclosed herein do notshow any precipitation in a Fasted-State Simulated Gastric Fluid(FaSSGF) for a prolonged time. For example, the stable oral liquidpharmaceutical compositions disclosed herein do not show anyprecipitation in a Fasted-State Simulated Gastric Fluid (FaSSGF) for atleast 10 min, at least 20 min, at least 30 min, at least 40 min, atleast 50 min, at least 60 min, at least 90 min, at least 2 hr, at least3 hr, at least 4 hr, at least 5 hr, at least 6 hr, at least 12 hr, atleast 24 hr, or longer.

In some embodiments, the stable oral liquid pharmaceutical compositionsdisclosed herein do not show any precipitation in a low pH environment.For example, the stable oral liquid pharmaceutical compositionsdisclosed herein do not show any precipitation in a Fasted-StateSimulated Gastric Fluid (FaSSGF) at pH 1.0-6.0 for at least 10 min, atleast 20 min, at least 30 min, at least 40 min, at least 50 min, atleast 60 min, at least 90 min, at least 2 hr, at least 3 hr, at least 4hr, at least 5 hr, at least 6 hr, at least 12 hr, at least 24 hr, orlonger. In some embodiments, the stable oral liquid pharmaceuticalcompositions disclosed herein do not show any precipitation in aFasted-State Simulated Gastric Fluid (FaSSGF) at pH 1.0-5.0 for at least10 min, at least 20 min, at least 30 min, at least 40 min, at least 50min, at least 60 min, at least 90 min, at least 2 hr, at least 3 hr, atleast 4 hr, at least 5 hr, at least 6 hr, at least 12 hr, at least 24hr, or longer. In some embodiments, the stable oral liquidpharmaceutical compositions disclosed herein do not show anyprecipitation in a Fasted-State Simulated Gastric Fluid (FaSSGF) at pH1.0-4.0 for at least 10 min, at least 20 min, at least 30 min, at least40 min, at least 50 min, at least 60 min, at least 90 min, at least 2hr, at least 3 hr, at least 4 hr, at least 5 hr, at least 6 hr, at least12 hr, at least 24 hr, or longer. In some embodiments, the stable oralliquid pharmaceutical compositions disclosed herein do not show anyprecipitation in a Fasted-State Simulated Gastric Fluid (FaSSGF) at pH1.0-3.0 for at least 10 min, at least 20 min, at least 30 min, at least40 min, at least 50 min, at least 60 min, at least 90 min, at least 2hr, at least 3 hr, at least 4 hr, at least 5 hr, at least 6 hr, at least12 hr, at least 24 hr, or longer. In some embodiments, the stable oralliquid pharmaceutical compositions disclosed herein do not show anyprecipitation in a Fasted-State Simulated Gastric Fluid (FaSSGF) at pH2.0-3.0 for at least 10 min, at least 20 min, at least 30 min, at least40 min, at least 50 min, at least 60 min, at least 90 min, at least 2hr, at least 3 hr, at least 4 hr, at least 5 hr, at least 6 hr, at least12 hr, at least 24 hr, or longer. In some embodiments, the stable oralliquid pharmaceutical compositions disclosed herein do not show anyprecipitation in a Fasted-State Simulated Gastric Fluid (FaSSGF) at pH2.0 for at least 10 min, at least 20 min, at least 30 min, at least 40min, at least 50 min, at least 60 min, at least 90 min, at least 2 hr,at least 3 hr, at least 4 hr, at least 5 hr, at least 6 hr, at least 12hr, at least 24 hr, or longer.

Without being bound by any particular theory, the stable oral liquidpharmaceutical compositions disclosed herein are essentially free of anyprecipitation inhibitors. In some embodiments, the stable oral liquidpharmaceutical compositions disclosed herein are completely free of anyprecipitation inhibitors. In some embodiments, the celecoxib compositionof present application is essentially free of precipitation inhibitorssuch as, polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethylcellulose. In some embodiments, the celecoxib compositions of thepresent application are essentially free of precipitation inhibitorsincluding: polyvinyl caprolactam-polyvinyl acetate-polyethylene glycolgraft copolymer (SOLUPLUS®), polyoxyethylene-polyoxypropylene blockcopolymers, pluronics, polyvinylpyrrolidone, cellulosic polymers,including hydroxypropyl cellulose and hydroxypropyl methylcellulose, andnon-cellulosic polymers.

In some embodiments, the present application provides a stable oralpharmaceutical composition comprising therapeutically effective amountof celecoxib, wherein said composition provides mean oil droplet size ofno more than 500 nm, when tested in 250 ml of Fasted-State SimulatedGastric Fluid (FaSSGF) at pH of 2.0, temperature of 37° C.±0.5° C. andunder stirring at a speed of 50 rpm.

In some embodiments, the present application provides a stable oralpharmaceutical composition comprising therapeutically effective amountof celecoxib, wherein said composition does not show any precipitationin the dissolution medium or Fasted-State Simulated Gastric Fluid(FaSSGF) at pH of 2.0, temperature of 37° C.±0.5° C. and under stirringat a speed of 50 rpm, when measured at 30 min or 60 min or 90 min or 120minutes or 180 minutes or 240 minutes time points; and said compositionis essentially free of precipitation inhibitors such as,polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethylcellulose.

In some embodiments, the present application provides a stable oralliquid pharmaceutical composition comprising therapeutically effectiveamount of celecoxib, wherein said composition does not show anyprecipitation in Fasted-State Simulated Gastric Fluid (FaSSGF) at pH of2.0, temperature of 37° C.±0.5° C. and under stirring at a speed of 50rpm, when measured at 30 min or 60 min or 90 min or 120 minutes or 180minutes or 240 minutes time points; and said composition is essentiallyfree of precipitation inhibitors such as,polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethylcellulose.

In some embodiments, the present application provides a stable oralpharmaceutical composition comprising therapeutically effective amountof celecoxib, at least one solubiliser, at least one medium chainglyceride, at least one polar solvent and at least one pharmaceuticallyacceptable excipients, wherein said composition does not show anyprecipitation in Fasted-State Simulated Gastric Fluid (FaSSGF) at pH of2.0, temperature of 37° C.±0.5° C. and under stirring at a speed of 50rpm, when measured at 30 min or 60 min or 90 min or 120 minutes or 180minutes or 240 minutes time points; and said composition is essentiallyfree of precipitation inhibitors such as,polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethylcellulose.

In some embodiments, the present application provides a stable oralliquid pharmaceutical composition comprising therapeutically effectiveamount of celecoxib, at least one solubiliser, at least one medium chainglyceride, at least one polar solvent and at least one pharmaceuticallyacceptable excipients, wherein said composition does not show anyprecipitation in Fasted-State Simulated Gastric Fluid (FaSSGF) at pH of2.0, temperature of 37° C.±0.5° C. and under stirring at a speed of 50rpm, when measured at 30 min or 60 min or 90 min or 120 minutes or 180minutes or 240 minutes time points; and said composition is essentiallyfree of precipitation inhibitors such as,polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethylcellulose.

The oral pharmaceutical celecoxib composition of present application canbe formulated in the form of a solution, suspension, emulsion or liquidmixture.

Medium Chain Glycerides

In some embodiments, the stable oral liquid pharmaceutical compositionsof the present application further comprise at least one medium chainglycerides. As used herein, a medium chain glyceride can refer to amedium chain mono-glyceride, a medium chain bi-glyceride, and/or amedium chain triglyceride (MCT). MCTs are triglycerides whose fattyacids have an aliphatic tail of 6-12 carbon atoms. MCTs are composed ofa glycerol backbone and three fatty acids. In the case of MCTs, 2 or 3of the fatty acid chains attached to glycerol are medium-chain inlength. Exemplary medium chain fatty acids include Caproic acid,Caprylic acid, Capric acid, Lauric acid, etc. It would be appreciatedthat the medium chain glycerides, such as MCTs, can improve thesolubility of the stable oral liquid pharmaceutical compositionsdisclosed herein when orally administered to the human subject, or in asimulated gastric fluid, e.g., Fasted-State Simulated Gastric Fluid(FaSSGF).

The medium chain glyceride may be present in the stable oral liquidpharmaceutical compositions disclosed herein in a variety ofconcentrations. For example, the stable oral liquid pharmaceuticalcompositions disclosed herein can comprise a medium chain glyceride ofat least 10% by weight, at least 20% by weight, at least 30% by weight,at least 40% by weight, at least 50% by weight, at least 60% by weight,at least 70% by weight, at least 80% by weight, at least 90% by weight,or a percentage between any two of the above values, based on the totalweight of the composition.

In some embodiments, the celecoxib compositions of present applicationcomprises of at least one medium chain glyceride in an amount of fromabout 5% to about 75% by weight, or from about 5% to about 65% byweight, or from about 5% to about 55% by weight, or from about 5% toabout 45% by weight, or from about 5% to about 35% by weight, based onthe total weight of the composition.

In some embodiments, the celecoxib compositions of present applicationfurther comprises of medium chain having at least one medium chain mono-or di- or tri-glyceride or mixtures thereof.

Suitable examples of medium chain mono- or di or tri-glyceride (MCT)used in the compositions of the present application are well known inthe art. The non-limiting examples of medium chain mono- or di ortri-glyceride (MCT) include, but are not limited to, both even and oddfatty acids, such as fatty acids containing C4 (butyric acid, butanoicacid), C5 (valeric acid), C6 (caproic acid, hexanoic acid), C7(heptanoic acid), C8 (caprylic acid, octanoic acid), C9 (pelargonicacid), C10 (capric acid, decanoic acid), C11 (undecanoic acid) or C12(lauric acid, dodecanoic acid) and both even and odd fatty acid(containing two to twelve carbon atoms) ester with glycerol such asglyceryl monocaprylate, glyceryl di-caprylate, propylene glycolheptanoate, glyceryl monocaprate, glyceryl caprylate/caprate, mediumchain mono- and diglycerides available as Capmul MCM®, propylene glycolmonocaprylate and di-caprylate, glyceryl tricaprylate, glyceroltricaprylate/caprate, glyceryl tricaprylate/tricaprate, glyceryltricaprylate/tricaprate PEG-8 Caprylic/Capric Glycerides, Further themedium chain glyceride component may be a naturally occurring mono- ordi or tri-glycerides containing composition, such as obtained frombutterfat, soy oil, coconut oil and the like.

In some embodiments, the celecoxib compositions of present applicationcomprises of at least one medium chain glycerides selected from thegroup of Lauroyl macrogolglycerides, Glyceryl Monocaprylate, GlycerylTricaprylate/Tricaprate or mixtures thereof.

Alternatively, said glyceride component may comprise at least oneindustrially prepared glycerides or a mixture of naturally occurring andindustrially prepared glycerides. Said glyceride may be prepared byinteresterification of C4 to C12 chain fatty acids such ascaprylocaproyl macrogol-8 glycerides.

Polar Solvents

In some embodiments, the stable oral liquid pharmaceutical compositionsof the present application further comprise at least one polar solvents.Without being bound by any particular theory, the addition of polarsolvent in the compositions of celecoxib as per present applicationadditionally helps in delaying the onset of precipitation time. In someembodiments, the onset of precipitation is delayed at least about 1-10hours compared to the compositions of celecoxib which are substantiallyfree of polar solvent. In some embodiments, the polar solvent can delaythe onset of precipitation time for at least about 1 hour, at leastabout 2 hours, at least about 3 hours, at least about 4 hours, at leastabout 5 hours, at least about 6 hours, or more.

Suitable examples of polar solvent that can be used in the presentapplication are selected from the group comprising propylene glycol,polyethylene glycols having a molecular weight between 400 and 1000,glycerin, C₂ to C₈ mono- and poly-alcohols such as ethanol, etc., C₇ toC₁₈ alcohols of linear or branched configuration, water and anycombination thereof.

The polar solvent may be present in the stable oral liquidpharmaceutical compositions disclosed herein in a variety ofconcentrations. For example, the stable oral liquid pharmaceuticalcompositions disclosed herein can comprise a polar solvent of at least10% by weight, at least 20% by weight, at least 30% by weight, at least40% by weight, at least 50% by weight, at least 60% by weight, at least70% by weight, at least 80% by weight, at least 90% by weight, or apercentage between any two of the above values, based on the totalweight of the composition.

In some embodiments, the celecoxib compositions of present applicationcomprises of polar solvent is in an amount of from about 20% to about80% by weight, or from about 20% to about 70% by weight or from about20% to about 60% by weight, or from about 20% to about 50% by weight, orfrom about 20% to about 40% by weight, based on the total weight of thecomposition.

Solubilisers

In some embodiments, the stable oral liquid pharmaceutical compositionsof the present application comprises of at least one solubilisersselected from the group of nonionic, anionic, cationic and zwitterionicsurfactants or mixtures thereof.

Suitable non-limiting examples of the solubiliser(s) used in thecompositions of the present application includes, but not limited to,polyethoxylated fatty acids like esters of lauric acid, oleic acid, andstearic acid, PEG-fatty acid diesters like PEG-20 dilaurate, PEG-fattyacid mono- and di-ester mixtures, alcohol-oil transesterificationproducts like PEG-35 castor oil, Polyoxy 35 castor oil, polyoxyl 40hydrogenated castor oil, etc., polyglycerized fatty acids likepolyglyceryl oleate, etc., propylene glycol fatty acid esters likepropylene glycol monolaurate etc, mixtures of propylene glycolesters-glycerol esters like oleic acid esters of propylene glycol andglycerol, etc., sterol and sterol derivatives like PEG-24 cholesterolether etc, polyethylene glycol sorbitan fatty acid esters like PEG-20sorbitan monolaurate etc, polyethylene glycol alkyl ethers like PEG-3oleyl ether, etc., sugar esters like sucrose monopalmitate etc,polyethylene glycol alkyl phenols like Octoxynol-1 etc, sorbitan fattyacid esters like sorbitan monolaurate, lower alcohol fatty acid esterslike ethyl oleate, etc., anionic surfactants include fatty acid saltsand bile salts. Additional exemplary solubilisers include, but are notlimited to: polyoxyethylene alkylethers; polyethylene glycol fatty acidesters; polyethylene glycol glycerol fatty acid esters; polyoxyethylenesorbitan fatty acid esters; polyglycerol fatty acid esters;polyoxyethylene glycerides; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils, alkylglucosides;alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides Ionicsurfactants include sodium oleate, sodium lauryl sulfate, sodium laurylsarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, and sodiumtaurocholate; Gelucire® 44/14, etc.

In some embodiments, the celecoxib compositions of present applicationcomprises at least one solubilisers selected from the group consistingof, glycerol polyethylene glycol ricinoleate, macrogolglycerolricinoleate Ph.Eur., polyoxyl 35 castor Oil lauroyl polyoxyl-32glycerides, lauroyl macrogol-32 glycerides, polyoxyl 40 hydrogenatedcastor oil, Polyoxy 35 castor oil, PEG-40 Hydrogenated Castor Oil, ormixtures thereof.

The at least one solubilisers may be present in the stable oral liquidpharmaceutical compositions disclosed herein in a variety ofconcentrations. For example, the stable oral liquid pharmaceuticalcompositions disclosed herein can comprise at least one solubilisers ofat least 10% by weight, at least 20% by weight, at least 30% by weight,at least 40% by weight, at least 50% by weight, at least 60% by weight,at least 70% by weight, at least 80% by weight, at least 90% by weight,or a percentage between any two of the above values, based on the totalweight of the composition. In some embodiments, the celecoxibcomposition of present application comprises of at least onesolubilisers in an amount of from about 10% to about 70% by weight, orfrom about 20% to about 60% by weight, or from about 20% to about 50% byweight, or from about 30% to about 40% by weight, based on the totalweight of the composition.

In certain aspects of the above embodiments, the celecoxib compositionof present application comprises solubiliser and polar solvent in aweight ratio of from about 0.60:1.00 to about 1.8:1.00.

In another aspect of above embodiments, the present application providesa stable liquid oral pharmaceutical composition of celecoxib comprisingtherapeutically effective amount of celecoxib, at least one solubiliserand at least one polar solvent, wherein said composition comprisessolubiliser and polar solvent in weight ratio of from about 0.60:1.00 toabout 1.8:1.00.

In certain aspects of the above embodiments, the present applicationprovides a stable oral liquid pharmaceutical composition of celecoxibcomprising therapeutically effective amount of celecoxib, at least onesolubiliser, at least one polar solvent and at least onepharmaceutically acceptable excipient, wherein said compositioncomprises solubiliser and polar solvent in weight ratio of from about0.60:1.00 to about 1.8:1.00.

In an aspect of the above embodiments, the compositions of the presentapplication comprises celecoxib in an amount of from about 1% to about80% by weight, or from about 2% to about 70% by weight, or from about 2%to about 50% by weight, or from about 20% to about 40% by weight, orfrom about 2% to about 8% by weight, based on the total weight of thecomposition.

In some embodiments, the present application provides a stable oralliquid oral pharmaceutical composition of celecoxib comprising,therapeutically effective amount of celecoxib, at least one solubiliserand at least one pharmaceutically acceptable excipients, wherein saidcomposition comprises solubiliser and celecoxib in weight ratio of fromabout 4.0:1.0 to about 20:1.0.

In some embodiments, the celecoxib compositions of present applicationcomprises of at least one medium chain glyceride and celecoxib in aweight ratio of from about 2.0:1.0 to about 20:1.0. In some embodiments,compositions of present application comprises of at least one mediumchain glyceride and celecoxib in a weight ratio of from about 2.0:1.0 toabout 10.0:1.0.

In some embodiments, the celecoxib compositions of present applicationcomprises of at least one solubiliser and at least one medium chainglyceride in a ratio of from about 0.05:1.0 to about 20:1.0. In someembodiment, celecoxib composition of present application comprises of atleast one solubiliser and at least one medium chain glyceride in a ratioof from about 0.05:1.0 to about 10.0:1.0.

In some embodiments, the celecoxib composition of present applicationcomprises of at least one solubiliser and celecoxib in a weight ratio offrom about 4.0:1.0 to about 20:1.0.

In some embodiments, the present application provides a pharmaceuticalcomposition of celecoxib comprising:

-   -   a. therapeutically effective amount of celecoxib;    -   b. at least one solubiliser in amount from about 35% w/w to        about 45% w/w;    -   c. at least one polar solvent in amount from about 25% w/w to        about 42% w/w; and    -   d. at least one pharmaceutically acceptable excipient,        wherein said solubiliser and polar solvent are present in the        ratio of from about 0.60:1.00 to about 1.8:1.00 and does not        show any precipitation in Fasted-State Simulated Gastric Fluid        (FaSSGF) at pH 2.0, temperature of 37° C.±0.5° C. and under        stirring at a speed of 50 rpm at least for 60 minutes.        Improved Pharmacokinetic Parameters

The stable oral liquid pharmaceutical compositions disclosed herein canhave a variety of pharmacokinetic parameters. In some embodiments, thestable oral liquid pharmaceutical compositions disclosed herein can havean improved pharmacokinetic parameter in comparison to a conventionalcelecoxib oral composition, such as AUC_((0-15min)), AUC_((0-30min)),AUC_((0-1hr)), AUC_((0-2hr)), AUC_((0-t)), AUC_((0-∞)), T_(lag),T_(max), etc.

In some embodiments, the stable oral liquid pharmaceutical compositionsdisclosed herein, upon oral administration to a human subject underfasting conditions provides T_(lag) of not more than 60 minutes, notmore than 30 minutes, not more than 20 minutes, not more than 10minutes, not more than 8 minutes, not more than 6 minutes, not more than5 minutes, not more than 4 minutes, not more than 3 minutes, not morethan 2 minutes, not more than 1 minutes, or less. In some embodiments,the stable oral liquid pharmaceutical compositions disclosed herein,upon oral administration to a human subject under fasting conditionsprovides T_(max) of less than about 120 minutes, less than about 90minutes, less than about 80 minutes, less than about 70 minutes, lessthan about 60 minutes, less than about 50 minutes, less than about 40minutes, less than about 30 minutes, less than about 20 minutes, orless. In some embodiments, the stable oral liquid pharmaceuticalcompositions disclosed herein, upon oral administration to a humansubject under fasting conditions provides AUC_((0-15min)) of at leastabout 1 ng·h/mL, at least about 2 ng·h/mL, at least about 5 ng·h/mL, atleast about 10 ng·h/mL, at least about 20 ng·h/mL, at least about 30ng·h/mL, at least about 40 ng·h/mL, at least about 50 ng·h/mL, at leastabout 100 ng·h/mL, at least about 200 ng·h/mL, or more, or a rangebetween any two of the above values. In some embodiments, the stableoral liquid pharmaceutical compositions disclosed herein, upon oraladministration to a human subject under fasting conditions providesAUC_((0-30min)) of at least about 10 ng·h/mL, at least about 20 ng·h/mL,at least about 30 ng·h/mL, at least about 40 ng·h/mL, at least about 50ng·h/mL, at least about 60 ng·h/mL, at least about 70 ng·h/mL, at leastabout 80 ng·h/mL, at least about 90 ng·h/mL, at least about 100 ng·h/mL,at least about 200 ng·h/mL, at least about 500 ng·h/mL, or more, or arange between any two of the above values. In some embodiments, thestable oral liquid pharmaceutical compositions disclosed herein, uponoral administration to a human subject under fasting conditions providesAUC_((0-1hr)) of at least about 100 ng·h/mL, at least about 200 ng·h/mL,at least about 300 ng·h/mL, at least about 400 ng·h/mL, at least about500 ng·h/mL, at least about 600 ng·h/mL, at least about 700 ng·h/mL, atleast about 800 ng·h/mL, at least about 900 ng·h/mL, at least about 1000ng·h/mL, at least about 1500 ng·h/mL, at least about 2000 ng·h/mL, atleast about 3000 ng·h/mL, at least about 4000 ng·h/mL, or more, or arange between any two of the above values. In some embodiments, thestable oral liquid pharmaceutical compositions disclosed herein, uponoral administration to a human subject under fasting conditions providesAUC_((0-2hr)) of at least about 500 ng·h/mL, at least about 600 ng·h/mL,at least about 700 ng·h/mL, at least about 800 ng·h/mL, at least about900 ng·h/mL, at least about 1000 ng·h/mL, at least about 1500 ng·h/mL,at least about 2000 ng·h/mL, at least about 3000 ng·h/mL, at least about4000 ng·h/mL, at least about 5000 ng·h/mL, at least about 6000 ng·h/mL,at least about 7000 ng·h/mL, at least about 8000 ng·h/mL, or more, or arange between any two of the above values. In some embodiments, thestable oral liquid pharmaceutical compositions disclosed herein, uponoral administration to a human subject under fasting conditions providesAUC_((0-t)) of at least about 500 ng·h/mL, at least about 600 ng·h/mL,at least about 700 ng·h/mL, at least about 800 ng·h/mL, at least about900 ng·h/mL, at least about 1000 ng·h/mL, at least about 1500 ng·h/mL,at least about 2000 ng·h/mL, at least about 3000 ng·h/mL, at least about4000 ng·h/mL, at least about 5000 ng·h/mL, at least about 6000 ng·h/mL,at least about 7000 ng·h/mL, at least about 8000 ng·h/mL, or more, or arange between any two of the above values. In some embodiments, thestable oral liquid pharmaceutical compositions disclosed herein, uponoral administration to a human subject under fasting conditions providesAUC_((0-∞)) of at least about 500 ng·h/mL, at least about 600 ng·h/mL,at least about 700 ng·h/mL, at least about 800 ng·h/mL, at least about900 ng·h/mL, at least about 1000 ng·h/mL, at least about 1500 ng·h/mL,at least about 2000 ng·h/mL, at least about 3000 ng·h/mL, at least about4000 ng·h/mL, at least about 5000 ng·h/mL, at least about 6000 ng·h/mL,at least about 7000 ng·h/mL, at least about 8000 ng·h/mL, or more, or arange between any two of the above values.

In some embodiments, the stable oral liquid pharmaceutical compositionsdisclosed herein, upon oral administration to a human subject underfasting conditions have a release rate of no less than 50%, no less than60%, no less than 70%, no less than 80%, no less than 90%, at a periodof 10 minutes. In some embodiments, the stable oral liquidpharmaceutical compositions disclosed herein, upon oral administrationto a human subject under fasting conditions have a release rate of noless than 50%, no less than 60%, no less than 70%, no less than 80%, noless than 90%, at a period of 15 minutes. In some embodiments, thestable oral liquid pharmaceutical compositions disclosed herein have arelease rate of no less than 50%, no less than 60%, no less than 70%, noless than 80%, no less than 90%, at a period of 10 minutes in 900 ml of0.01N HCl with 0.5% sodium lauryl sulphate (SLS), when tested in a USPType 2 apparatus with sinkers at 50 rpm and 37° C. In some embodiments,the stable oral liquid pharmaceutical compositions disclosed herein havea release rate of no less than 50%, no less than 60%, no less than 70%,no less than 80%, no less than 90%, at a period of 15 minutes in 900 mlof 0.01N HCl with 0.5% sodium lauryl sulphate (SLS), when tested in aUSP Type 2 apparatus with sinkers at 50 rpm and 37° C.

In some embodiments, the celecoxib compositions of present applicationcomprises reduced dose of celecoxib, wherein said composition providessimilar or higher AUC_(0-15min), AUC_(0-30min), AUC_(0-1hour), andAUC_(0-2hour), compared to conventional celecoxib compositions such asCELEBREX® oral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises reduced dose of celecoxib, wherein said composition providesAUC_(0-15min) of at least 50 times higher compared to conventionalcelecoxib compositions such as CELEBREX® oral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises reduced dose of celecoxib, wherein said composition providesAUC_(0-30min) of at least 12 times higher compared to conventionalcelecoxib compositions such as CELEBREX® oral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises reduced dose of celecoxib, wherein said composition providesAUC_(0-1hour) of at least 5 times higher compared to conventionalcelecoxib compositions such as CELEBREX® oral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises reduced dose of celecoxib, wherein said composition providesAUC_(0-2hour) of at least 1.5 times higher compared to conventionalcelecoxib compositions such as CELEBREX® oral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises reduced dose of celecoxib, wherein said composition providessimilar or higher AUC_(0-15min), AUC_(0-30min), AUC_(0-1hour), andAUC_(0-2hour), compared to conventional celecoxib compositionscomprising 400 mg of celecoxib such as CELEBREX® 400 mg oral capsules.

In some embodiments, the present application provides an oral liquidpharmaceutical composition comprising therapeutically effective amountof celecoxib, at least one solubiliser, at least one medium chainglyceride, at least one polar solvent and at least one pharmaceuticallyacceptable excipient, wherein said composition upon oral administrationto a human subject under fasting conditions provides at least one of thefollowing pharmacokinetic parameters:

a) AUC_((0-15min)) from about 10 ng·h/mL to about 80 ng·h/mL;

b) AUC_((0-30min)) from about 80 ng·h/mL to about 400 ng·h/mL;

c) AUC_((0-1hr)) from about 400 ng·h/mL to about 1500 ng·h/mL;

d) AUC_((0-2hr)) from about 1000 ng·h/mL to about 4000 ng·h/mL;

e) AUC_((0-t)) of at least about 2000 ng·h/mL;

f) AUC_((0-∞)) of at least about 2000 ng·h/mL; and

g) T_(lag) of not more than 8 minutes.

In some embodiments, the present application provides an oral liquidpharmaceutical composition comprising therapeutically effective amountof celecoxib, at least one solubiliser, at least one medium chainglyceride, at least one polar solvent and at least one pharmaceuticallyacceptable excipient, wherein said composition comprises solubiliser andpolar solvent in the ratio of from about 0.60:1.00 to about 1.8:1.00 andupon oral administration to a human subject under fasting conditionsprovides at least one of the following pharmacokinetic parameters:

a) AUC_((0-15min)) from about 10 ng·h/mL to about 80 ng·h/mL;

b) AUC_((0-30min)) from about 80 ng·h/mL to about 400 ng·h/mL;

c) AUC_((0-1hr)) from about 400 ng·h/mL to about 1500 ng·h/mL;

d) AUC_((0-2hr)) from about 1000 ng·h/mL to about 4000 ng·h/mL;

e) AUC_((0-t)) of at least about 2000 ng·h/mL;

f) AUC_((0-∞)) of at least about 2000 ng·h/mL; and

g) T_(lag) of not more than 8 minutes.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride and at least onepharmaceutically acceptable excipient; wherein said composition

a) releases no less than 70% at a period of 10 minutes; or

b) releases no less than 80% at a period of 15 minutes,

in 900 ml of 0.01N HCl with 0.5% sodium lauryl sulphate (SLS), whentested in a USP Type 2 apparatus with sinkers at 50 rpm and 37° C.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient; whereinsaid composition

a) releases no less than 70% at a period of 10 minutes; or

b) releases no less than 80% at a period of 15 minutes,

in 900 ml of 0.01N HCl with 0.5% sodium lauryl sulphate (SLS), whentested in a USP Type 2 apparatus with sinkers at 50 rpm and 37° C.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides AUC_((0-15min)) at least about 10 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides AUC_((0-15min)) from about 10 ng·h/mL toabout 80 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides AUC_((0-30min)) at least about 80 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides AUC_((0-30min)) from about 80 ng·h/mL toabout 400 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides AUC_((0-1hr)) at least about 400 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides AUC_((0-1hr)) from about 400 ng·h/mL toabout 1500 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides AUC_((0-2hr)) at least about 1000 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides AUC_((0-2hr)) from about 1000 ng·h/mL toabout 4000 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides AUC_((0-t)) of at least about 2000 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides AUC_((0-∞)) of at least about 2000 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides T_(lag) of not more than 10 minutes.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides T_(lag) of not more than 8 minutes.

In some embodiments, the celecoxib composition of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides T_(lag) of not more than 5 minutes.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides T_(max) of less than about 90 minutes.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition upon oral administration to a human subject underfasting conditions provides T_(max) of less than about 60 minutes.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition comprises solubiliser and polar solvent in the ratio offrom about 0.60:1.00 to about 1.8:1.00; and said composition upon oraladministration to a human subject under fasting conditions providesAUC_((0-15min)) at least about 10 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition comprises solubiliser and polar solvent in the ratio offrom about 0.60:1.00 to about 1.8:1.00; and said composition upon oraladministration to a human subject under fasting conditions providesAUC_((0-15min)) from about 10 ng·h/mL to about 80 ng·h/mL.

In some embodiments, the celecoxib compositions of celecoxib of thepresent application comprises of therapeutically effective amount ofcelecoxib, at least one solubiliser, at least one medium chainglyceride, at least one polar solvent and at least one opharmaceutically acceptable excipient, wherein said compositioncomprises solubiliser and polar solvent in the ratio of from about0.60:1.00 to about 1.8:1.00; and said composition upon oraladministration to a human subject under fasting conditions providesAUC_((0-30min)) at least about 80 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition comprises solubiliser and polar solvent in the ratio offrom about 0.60:1.00 to about 1.8:1.00; and said composition upon oraladministration to a human subject under fasting conditions providesAUC_((0-30min)) from about 80 ng·h/mL to about 400 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition comprises solubiliser and polar solvent in the ratio offrom about 0.60:1.00 to about 1.8:1.00; and said composition upon oraladministration to a human subject under fasting conditions providesAUC_((0-1hr)) at least about 400 ng·h/mL.

In some embodiments the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition comprises solubiliser and polar solvent in the ratio offrom about 0.60:1.00 to about 1.8:1.00; and said composition upon oraladministration to a human subject under fasting conditions providesAUC_((0-1hr)) from about 400 ng·h/mL to about 1500 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition comprises solubiliser and polar solvent in the ratio offrom about 0.60:1.00 to about 1.8:1.00; and said composition upon oraladministration to a human subject under fasting conditions providesAUC_((0-2hr)) at least about 1000 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition comprises solubiliser and polar solvent in the ratio offrom about 0.60:1.00 to about 1.8:1.00 and; said composition upon oraladministration to a human subject under fasting conditions providesAUC_((0-2hr)) from about 1000 ng·h/mL to about 4000 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition comprises solubiliser and polar solvent in the ratio offrom about 0.60:1.00 to about 1.8:1.00 and upon oral administration to ahuman subject under fasting conditions provides AUC_((0-t)) of at leastabout 2000 ng·h/mL.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition comprises solubiliser and polar solvent in the ratio offrom about 0.60:1.00 to about 1.8:1.00; and said composition upon oraladministration to a human subject under fasting conditions providesAUC_((0-∞)) of at least about 2000 ng·h/mL

In some embodiments, the compositions of celecoxib of the presentapplication comprises of therapeutically effective amount of celecoxib,at least one solubiliser, at least one medium chain glyceride, at leastone polar solvent and at least one pharmaceutically acceptableexcipient, wherein said composition comprises solubiliser and polarsolvent in the ratio of from about 0.60:1.00 to about 1.8:1.00; and saidcomposition upon oral administration to a human subject under fastingconditions provides T_(lag) of not more than 10 minutes.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition comprises solubiliser and polar solvent in the ratio offrom about 0.60:1.00 to about 1.8:1.00; and said composition upon oraladministration to a human subject under fasting conditions providesT_(lag) of not more than 8 minutes.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition comprises solubiliser and polar solvent in the ratio offrom about 0.60:1.00 to about 1.8:1.00; and said composition upon oraladministration to a human subject under fasting conditions providesT_(lag) of not more than 5 minutes.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition comprises solubiliser and polar solvent in the ratio offrom about 0.60:1.00 to about 1.8:1.00; and said composition upon oraladministration to a human subject under fasting conditions providesT_(max) of less than about 90 minutes.

Improved Physical Properties

In some embodiments, the stable oral liquid pharmaceutical compositionsdisclosed herein possess improved physical properties, such as dropletsize, viscosity, etc. The D50 and D90 represent, the median or the50^(th) percentile and the 90^(th) percentile of the oil droplet sizedistribution, respectively, as measured by volume. This means, the term“D50” is defined as the size in nm (nanometers) below which 50 percentof the oil droplets reside on a volume basis and similarly, the term“D90” is defined as the size in nm (nanometers) below which 90% of theoil droplets reside, on a volume basis. Oil droplet size can bedetermined, for example, by laser light scattering using a particle sizeanalyzer, such as the proprietary Zetasizer™ apparatus available fromMalvern Instruments Ltd.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride and at least onepharmaceutically acceptable excipient, wherein said compositions doesnot show any precipitation in Fasted-State Simulated Gastric Fluid(FaSSGF) at pH 2.0, temperature of 37° C.±0.5° C. and under stirring ata speed of 50 rpm at least for 60 minutes and said composition has amean oil droplet size of not more than 500 nm.

A ternary phase diagram is drawn (FIG. 1) which depicts the “stablecomposition region A”. The “stable composition region A” is defined byshaded region or the region between the connecting lines between sixpoints (a, b, c, d, e and f). Any composition that is outside of thisregion does not form an acceptable composition because either the onsetof precipitation time is less than 60 minutes; D50 oil droplet size ismore than about 250 nm or D90 oil droplet size is more than about 500nm.

In one embodiment, stable compositions of celecoxib as per presentapplication that comprises

-   -   a) therapeutically effective amount of celecoxib, at least one        solubiliser, at least one medium chain glyceride; and    -   b) polar solvent comprising mixture of ethanol and glycerin;        wherein the composition falls within the shaded region of a        phase diagram, as shown in FIG. 1, wherein boundaries of a        stable composition are defined by shaded region or the region        between the connecting lines between the six points (a, b, c, d,        e and f), wherein the composition comprises about 1% to about        80% w/w celecoxib and correspond to a weight % ratio of base        composition:ethanol:glycerin of 0.200:0.024:0.712 for a,        0.200:0.376:0.360 for b, 0.200:0.400:0.336 for c,        0.536:0.400:0.000 for d, 0.900:0.036:0.00 for e and        0.900:0.00:0.036 for f.

A ternary phase diagram is drawn FIG. 2 which depicts the “stablecomposition region B”. The “stable composition region B” is defined byshaded region or the region between the connecting lines between sixpoints (a, b, c, d, e and f). Any composition that is outside of thisregion does not form an acceptable composition because either the onsetof precipitation time is less than 60 minutes; D50 oil droplet size ismore than about 125 nm or D90 oil droplet size is more than about 250nm.

In one embodiment, stable compositions of celecoxib as per presentapplication that comprises

-   -   a) therapeutically effective amount of celecoxib, at least one        solubiliser, at least one medium chain glyceride; and    -   b) polar solvent comprising mixture of ethanol and glycerin;        wherein the composition falls within shaded region of a phase        diagram, as shown in FIG. 2, wherein boundaries of a stable        composition are defined by shaded region or the region between        the connecting lines between the six points (a, b, c, d, e and        f), wherein the composition comprises about 1% to about 80% w/w        celecoxib and correspond to a weight % ratio of base        composition:ethanol:glycerin of 0.226:0.000:0.710 for a,        0.235:0.371:0.330 for b, 0.236:0.400:0.300 for c,        0.536:0.400:0.000 for d, 0.865:0.071:0.000 for e and        0.836:0.000:0.100 for f.

A ternary phase diagram is drawn (FIG. 3) which depicts the “stablecomposition region C”. The “stable composition region C” is defined byshaded region or the region between the connecting lines between eightpoints (a, b, c, d, e, f, g and h). Any composition that is outside ofthis shaded region does not form an acceptable composition becauseeither the onset of precipitation time is less than 60 minutes; D50 oildroplet size is more than about 50 nm or D90 oil droplet size is morethan about 100 nm.

In one embodiment, stable compositions of celecoxib as per presentapplication that comprises

-   -   c) therapeutically effective amount of celecoxib, at least one        solubiliser, at least one medium chain glyceride; and    -   d) polar solvent comprising mixture of ethanol and glycerin;        wherein the composition falls within region of a phase diagram,        as shown in FIG. 3, wherein boundaries of a stable composition        are defined by shaded region or the region between the        connecting lines between the eight points (a, b, c, d, e, f, g        and h) wherein the composition comprises about 1% to about 80%        w/w celecoxib and correspond to a weight % ratio of base        composition:ethanol:glycerin is 0.300:0.000:0.636 for a,        0.385:0.206:0.345 for b, 0.283:0.399:0.254 for c,        0.536:0.400:0.000 for d, 0.745:0.191:0.000 for e,        0.778:0.144:0.014 for f, 0.817:0.056:0.063 for g and        0.636:0.000:0.300 for h.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B” and “stablecomposition region C” within the region of the phase diagrams, whereinthe compositions comprises reduced dose of celecoxib, wherein thereduced dose of celecoxib provides similar or higher AUC_(0-15min),AUC_(0-30min), AUC_(0-1hour), and AUC_(0-2hour) compared to conventionalcelecoxib compositions such as CELEBREX® oral capsules.

In another aspect of above embodiments, the stable compositions depictedby “stable composition region A”, “stable composition region B” and“stable composition region C” shown in the shaded region of the phasediagrams, wherein the compositions are essentially free of precipitationinhibitors such as, polyoxyethylene-polyoxypropylene block copolymers,pluronics, polyvinylpyrrolidone, hydroxypropyl cellulose andhydroxypropyl methylcellulose.

In another aspect of above embodiments, the stable compositions depictedby “stable composition region A”, “stable composition region B” and“stable composition region C” shown in the shaded region of the phasediagrams, wherein the compositions

a) releases no less than 70% at a period of 10 minutes; or

b) releases no less than 80% at a period of 15 minutes,

in 900 ml of 0.01N HCl with 0.5% sodium lauryl sulphate (SLS), whentested in a USP Type 2 apparatus with sinkers at 50 rpm and 37° C.

In another aspect of above embodiments, the stable compositions depictedby “stable composition region A”, “stable composition region B” and“stable composition region C” shown in the shaded region of the phasediagrams, wherein said composition in the form of a solution,suspension, emulsion or liquid mixture.

In another aspect of above embodiments, the stable compositions depictedby “stable composition region A”, “stable composition region B” and“stable composition region C” shown in the shaded region of the phasediagrams, wherein said composition has a viscosity of from about 20 cpsto about 1000 cps and has a density of from about 0.8 gm/cm³ to about 2gm/cm³.

In another aspect of above embodiments, the stable compositions depictedby “stable composition region A”, “stable composition region B” and“stable composition region C” shown in the shaded region of the phasediagrams, wherein the composition has transmittance of at least 40%.

In another aspect of above embodiments, the stable compositions depictedby “stable composition region A”, “stable composition region B” and“stable composition region C” shown in the shaded region of the phasediagrams, wherein the composition has pH of from about 3 to about 7.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B” and “stablecomposition region C” shown in the shaded region of the phase diagrams,wherein said composition

c) releases no less than 70% at a period of 10 minutes; or

a) releases no less than 80% at a period of 15 minutes,

in 900 ml of 0.01N HCl with 0.5% sodium lauryl sulphate (SLS), whentested in a USP Type 2 apparatus with sinkers at 50 rpm and 37° C.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B” and “stablecomposition region C” shown in the shaded region of a phase diagrams,wherein the composition upon oral administration to a human subjectunder fasting conditions provides AUC_((0-15min)) at least about 10ng·h/mL.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B”, “and “stablecomposition region C” shown in the shaded region of a phase diagram,wherein the composition upon oral administration to a human subjectunder fasting conditions provides AUC_((0-15min)) from about 10 ng·h/mLto about 80 ng·h/mL.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B” and “stablecomposition region C” shown in the shaded region of the phase diagram,wherein said composition upon oral administration to a human subjectunder fasting conditions provides AUC_((0-30min)) at least about 80ng·h/mL.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B” and “stablecomposition region C” shown in the shaded region of the phase diagrams,wherein said composition upon oral administration to a human subjectunder fasting conditions provides AUC_((0-30min)) from about 80 ng·h/mLto about 400 ng·h/mL.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B” and “stablecomposition region C” shown in the shaded region of the phase diagrams,wherein said composition upon oral administration to a human subjectunder fasting conditions provides AUC_((0-1hr)) at least about 400ng·h/mL.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B” and “stablecomposition region C” shown in the shaded region of a phase diagrams,wherein said composition upon oral administration to a human subjectunder fasting conditions provides AUC(0-1 hr) from about 400 ng·h/mL toabout 1500 ng·h/mL.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B” and “stablecomposition region C” shown in the shaded region of a phase diagrams,wherein said composition upon oral administration to a human subjectunder fasting conditions provides AUC_((0-2hr)) at least about 1000ng·h/mL.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B” and “stablecomposition region C” shown in the shaded region of a phase diagrams,wherein said composition upon oral administration to a human subjectunder fasting conditions provides AUC(0-2 hr) from about 1000 ng·h/mL toabout 4000 ng·h/mL.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B” and “stablecomposition region C” shown in the shaded region of a phase diagrams,wherein said composition upon oral administration to a human subjectunder fasting conditions provides AUC(0-t) of at least about 2000ng·h/mL.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B” and “stablecomposition region C” shown in the shaded region of a phase diagrams,wherein said composition upon oral administration to a human subjectunder fasting conditions provides AUC_((0-∞)) of at least about 2000ng·h/mL.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B” and “stablecomposition region C” shown in the shaded region of a phase diagrams,wherein said composition upon oral administration to a human subjectunder fasting conditions provides T_(lag) of not more than 8 minutes.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B” and “stablecomposition region C” shown in the shaded region of a phase diagrams,wherein said composition upon oral administration to a human subjectunder fasting conditions provides Tmax of less than about 90 minutes.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B”, and “stablecomposition region C” shown in the shaded region of a phase diagrams,wherein said composition upon oral administration to a human subjectunder fasting conditions provides at least one of the followingpharmacokinetic parameters:

a) AUC_((0-15min)) from about 10 ng·h/mL to about 80 ng·h/mL;

b) AUC_((0-30min)) from about 80 ng·h/mL to about 400 ng·h/mL;

c) AUC_((0-1hr)) from about 400 ng·h/mL to about 1500 ng·h/mL;

d) AUC_((0-2hr)) from about 1000 ng·h/mL to about 4000 ng·h/mL;

e) AUC_((0-t)) of at least about 2000 ng·h/mL;

f) AUC_((0-∞)) of at least about 2000 ng·h/mL; and

g) T_(lag) of not more than 8 minutes.

In some embodiments, the stable compositions depicted by “stablecomposition region A”, “stable composition region B”, and “stablecomposition region C” shown in the shaded region of a phase diagrams,wherein said composition comprising reduced dose of celecoxib upon oraladministration to a human subject under fasting conditions provides atleast one of the following pharmacokinetic parameters:

a) AUC_((0-15min)) from about 10 ng·h/mL to about 80 ng·h/mL;

b) AUC_((0-30min)) from about 80 ng·h/mL to about 400 ng·h/mL;

c) AUC_((0-1hr)) from about 400 ng·h/mL to about 1500 ng·h/mL;

d) AUC_((0-2hr)) from about 1000 ng·h/mL to about 4000 ng·h/mL;

e) AUC_((0-t)) of at least about 2000 ng·h/mL;

f) AUC_((0-∞)) of at least about 2000 ng·h/mL; and

g) T_(lag) of not more than 8 minutes.

The stable oral liquid pharmaceutical compositions disclosed herein cancomprise a variety of mean oil droplet sizes. In some embodiments, thecomposition provides mean oil droplet size of not more than 500 nm, notmore than 250 nm, not more than 100 nm, not more than 50 nm.

In some embodiments, the celecoxib composition of present application isstable and does not show any precipitation in Fasted-State SimulatedGastric Fluid (FaSSGF) at pH 2.0, temperature of 37° C.±0.5° C. andunder stirring at a speed of 50 rpm at least for 60 minutes and saidcomposition has a mean oil droplet size of not more than 500 nm.

In some embodiments, the celecoxib composition of present application isstable and does not show any precipitation in Fasted-State SimulatedGastric Fluid (FaSSGF) at pH 2.0, temperature of 37° C.±0.5° C. andunder stirring at a speed of 50 rpm at least for 60 minutes and saidcomposition has a mean oil droplet size of not more than 250 nm.

In some embodiments, the celecoxib composition of present application isstable and does not show any precipitation in Fasted-State SimulatedGastric Fluid (FaSSGF) at pH 2.0, temperature of 37° C.±0.5° C. andunder stirring at a speed of 50 rpm at least for 60 minutes and saidcomposition has a mean oil droplet size of not more than 100 nm.

In some embodiments, the celecoxib composition of present application isstable and does not show any precipitation in Fasted-State SimulatedGastric Fluid (FaSSGF) at pH 2.0, temperature of 37° C.±0.5° C. andunder stirring at a speed of 50 rpm at least for 60 minutes and saidcomposition has a mean oil droplet size of composition is not more than50 nm.

The stable oral liquid pharmaceutical compositions disclosed herein cancomprise a variety of viscosities. In some embodiments, the stable oralliquid composition of celecoxib of the present application has aviscosity that is about 20 cps, about 40 cps, about 60 cps, about 80cps, about 100 cps, about 200 cps, about 500 cps, about 1000 cps, or arange between any two of the above values.

The stable oral liquid pharmaceutical compositions disclosed herein cancomprise a variety of densities. In some embodiments, the stable oralliquid composition of celecoxib of the present application has a densityof from about 0.8 gm/cm³ to about 2 gm/cm³.

In some embodiment, the composition provides mean oil droplet size ofnot more than 500 nm or not more than 250 nm or not more than 100 nm ornot more than 50 nm.

In some embodiments, the stable oral liquid composition of the presentapplication has a viscosity of from about 20 cps to about 1000 cps.

In some embodiments, the stable oral liquid composition of the presentapplication has a density of from about 0.8 gm/cm³ to about 2 gm/cm³.

In some embodiments, the stable oral liquid composition of the presentapplication has transmittance of at least 40%.

In some embodiments, the stable oral liquid composition of the presentapplication has a pH of from about 3 to about 7.

In some embodiments, the celecoxib compositions of present applicationfurther comprises of water in amount less than about 10%, based on totalweight of the composition.

The stable oral liquid pharmaceutical compositions disclosed herein cancomprise a variety of transmittances. In some embodiments, the stableoral liquid composition of celecoxib of present application hastransmittance of at least 40%. In some embodiments, the stable oralliquid composition of celecoxib of present application has transmittanceof more than 40%.

The stable oral liquid pharmaceutical compositions disclosed herein cancomprise a variety of pH values. In some embodiments, the stable oralliquid composition of celecoxib of present application has pH of fromabout 3 to about 7.

In some embodiments, the present application provides an stable oralliquid pharmaceutical composition of celecoxib comprising:

-   -   a. therapeutically effective amount of celecoxib;    -   b. at least one solubiliser in amount from about 35% w/w to        about 45 w/w;    -   c. at least one polar solvent in amount from about 25% w/w to        about 42% w/w; and    -   d. at least one pharmaceutically acceptable excipient,        wherein said solubiliser and polar solvent are present in the        ratio of from about 0.60:1.00 to about 1.8:1.00 and wherein said        composition has a viscosity of from about 20 cps to about 1000        cps and density of from about 0.8 gm/cm³ to about 2 gm/cm³.        Improved Stability

In some embodiments, present application relates to a compositioncomprising therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride and at least onepharmaceutically acceptable excipients, wherein said composition doesnot show any precipitation in Fasted-State Simulated Gastric Fluid(FaSSGF) at pH 2.0, temperature of 37° C.±0.5° C. and under stirring ata speed of 50 rpm at least for 60 minutes.

In some embodiments, the stable oral liquid composition of celecoxib ofthe present application is essentially free of precipitation inhibitorssuch as, polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethylcellulose.

In some embodiments, the present application provides a stable oralpharmaceutical composition comprising therapeutically effective amountof celecoxib, at least one solubiliser, at least one medium chainglyceride and at least one pharmaceutically acceptable excipients,wherein said composition does not show any precipitation in Fasted-StateSimulated Gastric Fluid (FaSSGF) at pH of 2.0, temperature of 37°C.±0.5° C. and under stirring at a speed of 50 rpm, when measured at 30min or 60 min or 90 min or 120 minutes or 180 minutes or 240 minutestime points; and said composition is essentially free of precipitationinhibitors such as, polyoxyethylene-polyoxypropylene block copolymers,pluronics, polyvinylpyrrolidone, hydroxypropyl cellulose andhydroxypropyl methylcellulose.

In some embodiments, the present application provides a stable oralliquid pharmaceutical composition comprising therapeutically effectiveamount of celecoxib, at least one solubiliser, at least one medium chainglyceride and at least one pharmaceutically acceptable excipients,wherein said composition does not show any precipitation in Fasted-StateSimulated Gastric Fluid (FaSSGF) at pH of 2.0, temperature of 37°C.±0.5° C. and under stirring at a speed of 50 rpm, when measured at 30min or 60 min or 90 min or 120 minutes or 180 minutes or 240 minutestime points; and said composition is essentially free of precipitationinhibitors such as, polyoxyethylene-polyoxypropylene block copolymers,pluronics, polyvinylpyrrolidone, hydroxypropyl cellulose andhydroxypropyl methylcellulose.

In some embodiment, the composition provides mean oil droplet size ofnot more than 500 nm or not more than 250 nm or not more than 100 nm ornot more than 50 nm.

In some embodiments, the stable oral liquid composition of the presentapplication has a viscosity of from about 20 cps to about 1000 cps.

In some embodiments, the stable oral liquid composition of the presentapplication has a density of from about 0.8 gm/cm³ to about 2 gm/cm³.

In some embodiments, the stable oral liquid composition of the presentapplication has transmittance of at least 40%.

In some embodiments, the stable oral liquid composition of the presentapplication has a pH of from about 3 to about 7.

In some embodiments, the present application provides an stable oralliquid pharmaceutical composition of celecoxib comprising:

-   -   a. therapeutically effective amount of celecoxib;    -   b. at least one solubiliser in amount from about 35% w/w to        about 45% w/w;    -   c. at least one polar solvent in amount from about 25% w/w to        about 42% w/w; and    -   d. at least one pharmaceutically acceptable excipient,        wherein said solubiliser and polar solvent are present in the        ratio of from about 0.60:1.00 to about 1.8:1.00 and shows no        precipitation in Fasted-State Simulated Gastric Fluid (FaSSGF)        at pH 2.0, temperature of 37° C.±0.5° C. and under stirring at a        speed of 50 rpm at least for 60 minutes.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser and at least one medium chain glyceride, wherein saidcomposition shows no precipitation in Fasted-State Simulated GastricFluid (FaSSGF) at pH 2.0, temperature of 37° C.±0.5° C. and understirring at a speed of 50 rpm at least for 60 minutes.

In some embodiments, present application relates to a compositioncomprising therapeutically effective amount of celecoxib, at least onesolubiliser and at least one pharmaceutically acceptable excipients,wherein said composition does not show any precipitation in Fasted-StateSimulated Gastric Fluid (FaSSGF) at pH 2.0, temperature of 37° C.±0.5°C. and under stirring at a speed of 50 rpm at least for 60 minutes.

In some embodiments, the present application provides a stable oralpharmaceutical composition comprising therapeutically effective amountof celecoxib, at least one solubiliser and at least one pharmaceuticallyacceptable excipients, wherein said composition does not show anyprecipitation in Fasted-State Simulated Gastric Fluid (FaSSGF) at pH of2.0, temperature of 37° C.±0.5° C. and under stirring at a speed of 50rpm, when measured at 30 min or 60 min or 90 min or 120 minutes or 180minutes or 240 minutes time points; and said composition is essentiallyfree of precipitation inhibitors such as,polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethylcellulose.

In some embodiments, the present application provides a stable oralliquid pharmaceutical composition comprising therapeutically effectiveamount of celecoxib, at least one solubiliser and at least onepharmaceutically acceptable excipients, wherein said composition doesnot show any precipitation in Fasted-State Simulated Gastric Fluid(FaSSGF) at pH of 2.0, temperature of 37° C.±0.5° C. and under stirringat a speed of 50 rpm, when measured at 30 min or 60 min or 90 min or 120minutes or 180 minutes or 240 minutes time points; and said compositionis essentially free of precipitation inhibitors such as,polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethylcellulose.

In some embodiments, the present application provides a pharmaceuticalcomposition comprising therapeutically effective amount of celecoxib, atleast one solubiliser, at least one polar solvent and at least onepharmaceutically acceptable excipient, wherein said composition does notshow any precipitation in Fasted-State Simulated Gastric Fluid (FaSSGF)at pH 2.0, temperature of 37° C.±0.5° C. and under stirring at a speedof 50 rpm at least for 60 minutes.

In some embodiments, the present application provides a stable oralpharmaceutical composition comprising therapeutically effective amountof celecoxib, at least one solubiliser, at least one medium chainglyceride, at least one polar solvent and at least one pharmaceuticallyacceptable excipients, wherein said composition does not show anyprecipitation in Fasted-State Simulated Gastric Fluid (FaSSGF) at pH of2.0, temperature of 37° C.±0.5° C. and under stirring at a speed of 50rpm, when measured at 30 min or 60 min or 90 min or 120 minutes or 180minutes or 240 minutes time points; and said composition is essentiallyfree of precipitation inhibitors such as,polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethylcellulose.

In some embodiments, the present application provides a stable oralliquid pharmaceutical composition comprising therapeutically effectiveamount of celecoxib, at least one solubiliser, at least one medium chainglyceride, at least one polar solvent and at least one pharmaceuticallyacceptable excipients, wherein said composition does not show anyprecipitation in Fasted-State Simulated Gastric Fluid (FaSSGF) at pH of2.0, temperature of 37° C.±0.5° C. and under stirring at a speed of 50rpm, when measured at 30 min or 60 min or 90 min or 120 minutes or 180minutes or 240 minutes time points; and said composition is essentiallyfree of precipitation inhibitors such as,polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethylcellulose.

In some embodiments, the oral liquid composition of present applicationhas a viscosity of from about 20 cps to about 1000 cps.

In some embodiments, the oral liquid composition of present applicationhas a density of from about 0.8 gm/cm3 to about 2 gm/cm3.

In some embodiments, the celecoxib composition of present application donot show any precipitation in Fasted-State Simulated Gastric Fluid(FaSSGF) at pH 2.0, temperature of 37° C.±0.5° C. and under stirring ata speed of 50 rpm at least for 240 minutes.

In some embodiments, the celecoxib composition of present application isessentially free of precipitation inhibitors such as,polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethylcellulose.

In some embodiments, the present application provides a compositioncomprising therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient; whereinsaid composition provides mean oil droplet size of no more than 500 nm,when subjected to Fasted-State Simulated Gastric Fluid (FaSSGF) at pH of2.0, temperature of 37° C.±0.5° C. and under stirring at a speed of 50rpm, measured at 30 min or 60 min or 90 min or 120 minutes or 180minutes or 240 minutes time points.

In some embodiments, the celecoxib compositions of present applicationcomprises of therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, andwherein said composition does not show any precipitation in Fasted-StateSimulated Gastric Fluid (FaSSGF) at pH 2.0, temperature of 37° C.±0.5°C. and under stirring at a speed of 50 rpm at least for 240 minutes.

Reduced Dose

It is observed that the oral liquid celecoxib composition of presentapplication exhibits increased bioavailability (AUC_(0-15min),AUC_(0-30min), AUC_(0-1hour), AUC_(0-2hour)) and require smaller dose ascompared to conventional composition of celecoxib such as CELEBREX® oralcapsules. Thus, oral compositions with lower dose or reduced dose ofcelecoxib that can achieve the same or better therapeutic effects asobserved with larger doses of conventional celecoxib compositions aredesired to minimize the adverse effects of celecoxib.

In some embodiments, the compositions of celecoxib of the presentapplication comprises reduced dose of celecoxib, wherein reduced dose ofcelecoxib provides the same or better therapeutic effects compared toconventional composition of celecoxib such as CELEBREX® oral capsules.

In some embodiments, the compositions of celecoxib of the presentapplication comprises reduced dose of celecoxib, wherein reduced dose ofcelecoxib provides similar or higher AUC_(0-15min), AUC_(0-30min),AUC_(0-1hour), and AUC_(0-2hour) compared to conventional composition ofcelecoxib such as CELEBREX® oral.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein the reduction in dose ofcelecoxib is at least 20% compared to conventional celecoxibcompositions such as CELEBREX® oral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein the reduction in dose ofcelecoxib is at least 30% compared to conventional celecoxibcompositions such as CELEBREX® oral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein the reduction in dose ofcelecoxib is at least 40% compared to conventional celecoxibcompositions such as CELEBREX® oral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein the reduction in dose ofcelecoxib is at least 50% compared to conventional celecoxibcompositions such as CELEBREX® oral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein the reduction in dose ofcelecoxib is at least 60% compared to conventional celecoxibcompositions such as CELEBREX® oral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein the reduction in dose ofcelecoxib is at least 70% compared to conventional celecoxibcompositions such as CELEBREX® oral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein the reduction in dose ofcelecoxib is at least 80% compared to conventional celecoxibcompositions such as CELEBREX® oral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein the reduction in dose ofcelecoxib is at least 40% compared to conventional celecoxibcompositions comprising 400 mg of celecoxib such as CELEBREX® 400 mgoral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein the reduction in dose ofcelecoxib is at least 55% compared to conventional celecoxibcompositions comprising 400 mg of celecoxib such as CELEBREX® 400 mgoral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein the reduction in dose ofcelecoxib is at least 70% compared to conventional celecoxibcompositions comprising 400 mg of celecoxib such as CELEBREX® 400 mgoral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises reduced dose of celecoxib, wherein said reduced dose is fromabout 100 mg to 250 mg of celecoxib.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein said reduced dose isabout 240 mg.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein said reduced dose isabout 180 mg.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein said reduced dose isabout 120 mg.

In some embodiments, the celecoxib compositions of present applicationcomprises of reduced dose of celecoxib, wherein the reduction in dose ofcelecoxib is at least 70% compared to conventional celecoxibcompositions comprising 400 mg of celecoxib such as CELEBREX® 400 mgoral capsules.

In some embodiments, the celecoxib compositions of present applicationcomprises reduced dose of celecoxib, wherein said reduced dose is fromabout 100 mg to 250 mg of celecoxib.

In some embodiments, the stable oral liquid celecoxib composition ofpresent application is essentially free of precipitation inhibitors suchas, polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethylcellulose.

In some embodiments, the present application provides an oral liquidpharmaceutical composition comprises reduced dose of celecoxib, where inthe said reduced dose comprises of from about 100 mg to 250 mg ofcelecoxib, at least one solubiliser, at least one medium chainglyceride, at least one polar solvent and at least one pharmaceuticallyacceptable excipient, wherein said composition upon oral administrationto a human subject under fasting conditions provides at least one of thefollowing pharmacokinetic parameters:

a) AUC_((0-15min)) from about 10 ng·h/mL to about 80 ng·h/mL;

b) AUC_((0-30min)) from about 80 ng·h/mL to about 400 ng·h/mL;

c) AUC_((0-1hr)) from about 400 ng·h/mL to about 1500 ng·h/mL;

d) AUC_((0-2hr)) from about 1000 ng·h/mL to about 4000 ng·h/mL;

e) AUC_((0-t)) of at least about 2000 ng·h/mL;

f) AUC_((0-∞)) of at least about 2000 ng·h/mL; and

g) T_(lag) of not more than 8 minutes.

In some embodiments, the present application provides an oral liquidpharmaceutical composition comprise reduced dose of celecoxib, where inthe said low dose comprises of from about 100 mg to 250 mg of celecoxib,at least one solubiliser, at least one medium chain glyceride, at leastone polar solvent and at least one pharmaceutically acceptableexcipient, wherein said composition comprises solubiliser and polarsolvent in the ratio of from about 0.60:1.00 to about 1.8:1.00 and uponoral administration to a human subject under fasting conditions providesat least one of the following pharmacokinetic parameters:

a) AUC_((0-15min)) from about 10 ng·h/mL to about 80 ng·h/mL;

b) AUC_((0-30min)) from about 80 ng·h/mL to about 400 ng·h/mL;

c) AUC_((0-1hr)) from about 400 ng·h/mL to about 1500 ng·h/mL;

d) AUC_((0-2hr)) from about 1000 ng·h/mL to about 4000 ng·h/mL;

e) AUC_((0-t)) of at least about 2000 ng·h/mL;

f) AUC_((0-∞)) of at least about 2000 ng·h/mL; and

g) T_(lag) of not more than 8 minutes.

In some embodiments, the present application provides an oral liquidpharmaceutical composition of celecoxib, wherein said compositioncomprises of from about 100 mg to 250 mg of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipient, whereinsaid composition comprises solubiliser and polar solvent in the ratio offrom about 0.60:1.00 to about 1.8:1.00 and upon oral administration to ahuman subject under fasting conditions provides at least one of thefollowing pharmacokinetic parameters:

a) AUC_((0-15min)) from about 10 ng·h/mL to about 80 ng·h/mL;

b) AUC_((0-30min)) from about 80 ng·h/mL to about 400 ng·h/mL;

c) AUC_((0-1hr)) from about 400 ng·h/mL to about 1500 ng·h/mL;

d) AUC_((0-2hr)) from about 1000 ng·h/mL to about 4000 ng·h/mL;

e) AUC_((0-t)) of at least about 2000 ng·h/mL;

f) AUC_((0-∞)) of at least about 2000 ng·h/mL; and

g) T_(lag) of not more than 8 minutes.

Pharmaceutically Acceptable Excipients, Flavoring and Sweetening Agents

In some embodiments, the celecoxib compositions of present applicationmay further contain at least one flavoring agents or taste maskingagents. These flavoring agents or taste masking agents are well known inart or approved by US FDA.

Non-limiting exemplary list of flavoring agents/taste masking agents:natural and synthetic flavoring liquids such as volatile oils, syntheticflavor oils, flavoring aromatic and oils, liquids, oleoresins orextracts derived from plants, leaves, flowers, fruits, stems andcombinations thereof. Non-limiting representative examples of volatileoils include spearmint oil, cinnamon oil, oil of wintergreen (methylsalicylate), peppermint oil, menthol, clove oil, bay oil, anise oil,eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, allspice oil,oil of sage, mace extract, oil of bitter almond, and cassia oil. Alsoartificial, natural or synthetic flavors including fruit flavors such asvanilla, and citrus oils including lemon, orange, grape, lime andgrapefruit and fruit essences including apple, pear, peach, grape,strawberry, raspberry, cherry, plum, pineapple, apricot, banana andother useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral, i.e., alphocitral (lemon, lime),neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon),aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehydeC-12 (citrus fruits), tolyl aldehyde (cherry, almond),2,6-dimethyloctanal (green fruit), and 2-dodecenal (citrus, mandarin),bubble gum flavor, mixtures thereof and the like.

Non-limiting exemplary list of sweeteners: sugars such as sucrose,glucose (corn syrup), dextrose, invert sugar, fructose, and mixturesthereof, saccharin and its various salts such as the sodium or calciumsalt; cyclamic acid and its various salts such as the sodium salt; thedipeptide sweeteners such as aspartame, acesulfame K, and othersweeteners like magnasweet, sucralose, mixtures thereof and the like.

Methods of Treating Pain

In some embodiments, the present application relates to a method oftreating pain in a human subject by orally administering a stable oralliquid pharmaceutical composition as disclosed herein, In someembodiments, the composition comprises a therapeutically effectiveamount of celecoxib, at least one solubiliser, at least one medium chainglyceride and at least one pharmaceutically acceptable excipients,wherein said composition shows no precipitation in Fasted-StateSimulated Gastric Fluid (FaSSGF) at pH 2.0, temperature of 37° C.±0.5°C. and under stirring at a speed of 50 rpm at least for 60 minutes.

In some embodiments, the present application relates to a method oftreating pain in a human subject by orally administering a compositioncomprising therapeutically effective amount of celecoxib, at least onesolubiliser, at least one polar solvent, at least one medium chainglyceride and at least one pharmaceutically acceptable excipients,wherein said composition shows no precipitation in Fasted-StateSimulated Gastric Fluid (FaSSGF) at pH 2.0, temperature of 37° C.±0.5°C. and under stirring at a speed of 50 rpm at least for 60 minutes.

In some embodiment, the composition provides mean oil droplet size of nomore than 1000 nm or not more than 500 nm or not more than 250 nm or notmore than 100 nm or not more than 50 nm.

In some embodiments, the present application relates to a method fortreating pain in a human subject by orally administering a compositioncomprising therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride at least one polarsolvent and at least one pharmaceutically acceptable excipients, whereinsaid composition comprises of said solubiliser and polar solvent in theratio of from about 0.60:1.00 to about 1.8:1.00.

In some embodiments, the present application relates to a method fortreating pain in a human subject by orally administering a compositioncomprising therapeutically effective amount of celecoxib, at least onesolubiliser, at least one medium chain glyceride, at least one polarsolvent and at least one pharmaceutically acceptable excipients, whereinsaid composition is essentially free of precipitation inhibitors suchas, polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethylcellulose.

In some embodiments, the present application relates to a method fortreating pain in a human subject by orally administering a compositioncomprising therapeutically effective amount of celecoxib, wherein thecomposition has transmittance of at least 40%.

In some embodiments, the present application relates to a method fortreating pain in a human subject by orally administering a compositioncomprising therapeutically effective amount of celecoxib, wherein thecomposition has pH of from about 3 to about 7.

In some embodiments, the present application relates to a method fortreating pain in a human subject by administering an oral liquidpharmaceutical composition of celecoxib comprising:

-   -   a) therapeutically effective amount of celecoxib;    -   b) at least one solubiliser in an amount from about 35 w/w to        about 45 w/w; and    -   c) at least one polar solvent in an amount from about 25% w/w to        about 42% w/w;    -   d) at least one pharmaceutically acceptable excipients;        wherein said solubiliser and polar solvent are present in the        ratio of from about 0.60:1.00 to about 1.8:1.00 and wherein said        composition has a viscosity of from about 20 cps to about 1000        cps and density of from about 0.8 gm/cm³ to about 2 gm/cm³.

In some embodiments, the present application relates to a method fortreating pain in a human subject by administering an oral liquidpharmaceutical composition of celecoxib comprising:

-   -   a) reduced dose of celecoxib, wherein the reduction in dose of        celecoxib is at least 20 percent compared to conventional        celecoxib compositions;    -   b) at least one solubiliser in an amount from about 35 w/w to        about 45 w/w; and    -   c) at least one polar solvent in an amount from about 25% w/w to        about 42% w/w;    -   d) at least one pharmaceutically acceptable excipients;        wherein said solubiliser and polar solvent are present in the        ratio of from about 0.60:1.00 to about 1.8:1.00 and wherein said        composition has a viscosity of from about 20 cps to about 1000        cps and density of from about 0.8 gm/cm³ to about 2 gm/cm³.

In some embodiments, the present application relates to a method fortreating pain in a human subject by administering an oral liquidpharmaceutical composition of celecoxib, wherein said compositionprovides at least one of the following pharmacokinetic parameters uponoral administration to a human subject under fasting conditions:

a) AUC_((0-15min)) from about 10 ng·h/mL to about 80 ng·h/mL;

b) AUC_((0-30min)) from about 80 ng·h/mL to about 400 ng·h/mL;

c) AUC_((0-1hr)) from about 400 ng·h/mL to about 1500 ng·h/mL;

d) AUC_((0-2hr)) from about 1000 ng·h/mL to about 4000 ng·h/mL;

e) AUC_((0-t)) of at least about 2000 ng·h/mL;

f) AUC_((0-∞)) of at least about 2000 ng·h/mL; and

g) T_(lag) of not more than 8 minutes.

In some embodiments, the present application relates to a method fortreating pain in a human subject by orally administering a compositioncomprising therapeutically effective amount of celecoxib, wherein thecomposition has transmittance of at least 40%.

In some embodiments, the present application relates to a method fortreating pain in a human subject by orally administering a compositioncomprising therapeutically effective amount of celecoxib, wherein thecomposition has pH of from about 3 to about 7.

In some embodiments, the composition of present application is used forthe treatment or ameliorating of pain including, but not limited to,acute pain, migraine pain, cluster headache, neuropathic pain,post-operative pain, chronic lower back pain, herpes neuralgia, phantomlimb pain, central pain, dental pain, neuropathic pain, opioid-resistantpain, visceral pain, surgical pain, bone injury pain, arthritis pain,inflammation, osteoarthritis, juvenile rheumatoid arthritis, ankylosingspondylitis, primary dysmenorrhea, pain during labor and delivery, painresulting from burns, including sunburn, post-partum pain, angina pain,and genitourinary tract-related pain including cystitis, the term shallalso refer to nociceptive pain or nociception in patients need thereof.

Methods of Treating Migraine Pain

In some embodiments, the present application relates to a method oftreating migraine pain in a human subject by orally administering astable oral liquid pharmaceutical composition as disclosed herein, Insome embodiments, the methods lead to pain free at 2 hours in at least25%, at least 26%, at least 27%, at least 28%, at least 29%, at least30%, at least 31%, at least 32%, at least 33%, at least 34%, at least35%, or more, of the human subjects being treated. In some embodiments,the methods lead to an increase in the percentage of human subjectsbeing treated being pain free at 2 hours that is at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95%, or more, in comparison to the percentage of human subjects beingtreated with a placebo. In some embodiments, the methods lead to partialpain relief at 2 hours in at least 45%, at least 50%, at least 60%, atleast 65%, at least 66%, at least 67%, at least 68%, at least 69%, atleast 70%, at least 71%, at least 72%, at least 73%, at least 74%, atleast 75%, or more, of the human subjects being treated. In someembodiments, the methods lead to an increase in the percentage of humansubjects being treated being partially relieved of pain at 2 hours thatis at least 10%, at least 15%, at least 20%, at least 25%, at least 30%,at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, or more, in comparison to thepercentage of human subjects being treated with a placebo.

In some embodiments, the present application relates to a method oftreating migraine pain in a human subject by orally administering acomposition of Example 3 having 120 mg Celecoxib (Treatment-1). In someembodiments, the methods lead to pain free at 2 hours in at least 25%,at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, atleast 31%, at least 32%, at least 33%, at least 34%, at least 35%, ormore, of the human subjects being treated. In some embodiments, themethods lead to an increase in the percentage of human subjects beingtreated being pain free at 2 hours that is at least 40%, at least 45%,at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, ormore, in comparison to the percentage of human subjects being treatedwith a placebo. In some embodiments, the methods lead to partial painrelief at 2 hours in at least 45%, at least 50%, at least 60%, at least65%, at least 66%, at least 67%, at least 68%, at least 69%, at least70%, at least 71%, at least 72%, at least 73%, at least 74%, at least75%, or more, of the human subjects being treated. In some embodiments,the methods lead to an increase in the percentage of human subjectsbeing treated being partially relieved of pain at 2 hours that is atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, or more, in comparison to thepercentage of human subjects being treated with a placebo.

In some embodiments, the present application relates to methods,comprising administering a composition of Example 3 having 120 mgCelecoxib (Treatment-1), lead to pain free at 2 hours in at least 26%,at least 27%, at least 28% or at least 29% or at least 30% of the humansubjects being treated.

In some embodiments, the present application relates to methods,comprising administering a composition of Example 3 having 120 mgCelecoxib (Treatment-1), lead to partial pain relief at 2 hours in atleast at least 63% of the human subjects being treated.

In some embodiments, the methods of using a stable oral liquidpharmaceutical composition as disclosed herein, lead to an increase inthe percentage of human subjects being treated being pain free at 2hours that is at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, or more, incomparison to the percentage of human subjects being treated with acommercially available migraine pain treatment, such as VIOXX 25 (25mg), VIOXX 50 (50 mg) and CAMBIA 50 (50 mg). In some embodiments, themethods lead to an increase in the percentage of human subjects beingtreated being partially relieved of pain at 2 hours that is at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, at least 45%, at least 50%, at least 55%, at least60%, at least 65%, at least 70%, or more, in comparison to thepercentage of human subjects being treated with a commercially availablemigraine pain treatment, such as VIOXX 25 (25 mg), VIOXX 50 (50 mg) andCAMBIA 50 (50 mg). In some embodiments, the methods lead to an increasein the percentage of human subjects being treated being pain free at 2hours that is at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, or more, incomparison to the percentage of human subjects being treated with acommercially available migraine pain treatment, such as VIOXX 25 (25mg), VIOXX 50 (50 mg) and CAMBIA 50 (50 mg).

In some embodiments, the methods, comprising administering a compositionof Example 3 having 120 mg Celecoxib (Treatment-1), lead to an increasein the percentage of human subjects being treated being pain free at 2hours that is at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, or more, incomparison to the percentage of human subjects being treated with acommercially available migraine pain treatment, such as VIOXX 25 (25mg), VIOXX 50 (50 mg) and CAMBIA 50 (50 mg).

In some embodiments, the oral liquid compositions of the presentapplication can be dispensed in liquid form packaged in bottles or anyother suitable containers for oral administration. The liquidcomposition can be ingested with or without further mixing with aqueousor suitable media before oral administration.

In some embodiments, the oral liquid compositions of the presentapplication can be dispensed in container such as a sachet, ampoule,syringe or dropper device or tube or bottle, (for example, a tube orbottle which can be squeezed to deliver its contents), optionally as afixed dosage, the contents of which may be directly orally ingested ormixed or dispersed into food or liquid.

In some embodiments, the compositions of present application can beformulated as capsule that is suitable for oral administration. Thecomposition can be filled in hard or soft gelatin capsule or HPMCcapsules or capsules made up of any other pharmaceutically acceptablematerials.

In some embodiments, the composition of present application can besprayed on inert substrate which can be a powder or a multiparticulatesuch as a granule, a pellet, a bead, a spherule, a beadlet, amicrocapsule, a millisphere, a nanocapsule, a nanosphere or amicrosphere.

A substrate constitutes a finely divided (milled, micronized, nanosized,precipitated) form of an inert additive molecular aggregates or acompound aggregate of multiple components or a physical mixture ofaggregates of additives. Such substrates can be formed of variousmaterials known in the art, such as, for example: sugars, such aslactose, sucrose or dextrose; polysaccharides, such as maltodextrin ordextrates; starches; cellulosics, such as microcrystalline cellulose ormicrocrystalline cellulose/sodium carboxymethyl cellulose; inorganics,such as dicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc,or titania; and polyols, such as mannitol, xylitol, sorbitol orcyclodextrin.

EXAMPLES

The following examples are offered to illustrate but not to limit theinvention.

Although the invention has been illustrated by the following examples,it is not to be construed as being limited thereby; but rather, theinvention encompasses the generic area as hereinbefore disclosed.Various modifications and embodiments can be made without departing fromthe spirit and scope thereof.

Examples 1-3 Stable Oral Compositions of Celecoxib Used in the Studies

The compositions comprising celecoxib were prepared as given in Table 1.

TABLE 1 Stable oral liquid pharmaceutical compositions used in thestudies. Example 1 Example 2 Example 3 Ingredients (% w/w) (% w/w) (%w/w) Celecoxib 5.00 5.00 4.76 Lauroyl 4.17 10.00 9.52 macrogolglyceridesGlyceryl 5.00 5.00 4.76 Monocaprylate Glyceryl 12.50 12.50 11.90Tricaprylate/Tricaprate Polyoxy 35 castor oil 25.00 29.50 28.09 PEG-40Hydrogenated 10.33 0.00 0.00 Castor Oil Sweeteners 8.65 8.65 1.47 Propylgallate 0.02 0.02 0.00 Menthol 0.31 0.31 0.18 flavors 1.46 1.46 0.32Ethanol 20.00 20.00 0.00 Glycerine 5.21 5.21 0.00 Propylene glycol 0.000.00 33.87 Purified water q.s to 100 q.s to 100 q.s to 100

Manufacturing Procedure:

Celecoxib was added to solubilisers (lauroyl macrogolglycerides, polyoxy35 castor oil and PEG-40 Hydrogenated Castor Oil) and mixed properly toobtain uniform mixture.

Further to mixture of step 1 medium chain glycerides (caprylic/caprictriglyceride and glyceryl caprylate) were added.

To the mixture of step 2, other ingredients such as flavours andsweeteners were added and mixed well.

To the composition of step 3, propylene glycol was added and mixedthoroughly with slight heating 30° C.±5° C. until a uniform dispersionis obtained and cool the solution to 25-30° C. under stirring.

To the composition of step 4, purified water was added and mixed welluntil a clear solution obtained.

The composition of step 5 was filled in amber colored glass bottle with18 mm child resistant—tamper evident cap.

Example 4 Evaluation of Onset of Precipitation of the Stable OralComposition

Compositions of Examples 1, 2 & 3 were evaluated for onset ofprecipitation time.

2 ml of compositions comprising 100 mg of celecoxib were dropped in 250mL of FaSSGF, pH 2.0, at 37° C. under stirring and onset ofprecipitation was noted.

TABLE 2 Time for onset of precipitation. Time for onset of precipitation(minutes) Composition 30 60 120 180 240 Example 1 Precip- Precip-Precip- Precip- Precip- itation itation itation itation itation not notnot not not observed observed observed observed observed Example 2Precip- Precip- Precip- Precip- Precip- itation itation itation itationitation not not not not not observed observed observed observed observedExample 3 Precip- Precip- Precip- Precip- Precip- itation itationitation itation itation not not not not not observed observed observedobserved observed

Example 5 Evaluation of Dissolution Release Profile of the Stable OralCompositions

Celecoxib dissolution study of 2 ml of the compositions of Examples 1, 2& 3 comprising 100 mg of celecoxib was performed in a standard USPdissolution medium under the following conditions: USP apparatus IIpaddles; dissolution medium (900 ml 0.01N HCl containing 0.5% sodiumlauryl sulfate) at a speed of 50 rpm and a temperature of 37° C.

TABLE 3 Dissolution of the stable oral composition in standard USPdissolution medium. Sr. Time Example 1 Example 2 Example 3 No (mins) %Released 1 10 >70 >70 >70 2 15 >80 >80 >80

Example 6 Evaluation of Physical Properties of Stable Oral Compositions

The composition of Example 3 was found to be stable after subjecting itto stability evaluation conditions of 25° C./60% RH and 40° C./75% RH.The composition was also evaluated for viscosity, density, pH, oildroplet size.

TABLE 4 Physical evaluation of the stable oral composition. Storagecontainer Amber color glass bottle with cap 25° C./ 40° C./75% RH 60% RH1 2 3 3 Parameter Initial Month Month Month Month Assay 101.2 99.4 100102.6 103.3 pH 5.93 5.92 5.85 5.58 5.77 Sing high unknown 0.03 0.02 0.020.01 0.02 Total impurity 0.05 0.02 0.02 0.01 0.02 Density (g/ml) 1.011.01 1.01 1.011 1.017 Viscosity (cps) 129 108.9 104.6 101.6 127.7 D5018.4 18.1 18.7 18.4 18.1 oil droplet size D90 27.5 26.6 27.6 27.6 26.7oil droplet size

Example 7 Bioavailability of the Stable Oral Composition

A four-way, randomized, crossover study to compare the bioavailabilityof Example 3 (Celecoxib Oral Solution) at doses of 120 mg, 180 mg and240 mg versus CELEBREX® (celecoxib) 400 mg capsules and to determinedose-proportionality of Example 3 formulations in healthy volunteersunder fasting conditions.

In each study period, a single dose of celecoxib composition wasadministered orally, in the morning, following a 10-hour overnight fast.The administration is done as follows:

-   -   Treatment-1: Composition of Example 3 containing 120 mg of        Celecoxib, administered orally to the volunteers followed by        about 240 ml of water.    -   Treatment-2: Composition of Example 3 containing 180 mg of        Celecoxib, administered orally to the volunteers followed by        about 240 ml of water.    -   Treatment-3: Composition of Example 3 containing 240 mg of        Celecoxib, administered orally to the volunteers followed by        about 240 ml of water.    -   Treatment-4: An oral 400 mg dose (1×400 mg) CELEBREX® capsule        was administered with about 240 mL of water.        Results:

Celecoxib plasma concentrations and other pharmacokinetic parameterswere determined. Observed pharmacokinetic parameters are given in Table5.

TABLE 5 Pharmacokinetic parameters after administration of the stableoral composition. Treatment-1 Treatment-2 Treatment-3 Treatment-4 (Test120 mg) (Test 180 mg) (Test 240 mg) (Reference 400 mg) Parameters Mean ±SD Mean ± SD Mean ± SD Mean ± SD T lag^(a) 4.8 mins (0.0-7.2) 4.8 mins(0.0-7.2) 3.0 mins (0.0-7.2) 10.2 mins (4.8-19.8) T_(max) ^(a) (hrs)0.67 (0.50-1.67) 0.67 (0.50-1.03) 0.95 (0.50-2.00) 2.50 (1.67-5.00)C_(max) 1061.909 ± 237.632 1544.886 ± 289.851  1932.543 ± 305.703611.382 ± 222.223 (ng/mL) AUC₀_15 min  19.171 ± 10.697 26.616 ± 11.819 35.155 ± 17.795 0.300 ± 0.274 (ng · h/mL) AUC₀_30 min 149.120 ± 50.983227.989 ± 68.623  283.211 ± 80.932 9.491 ± 5.773 (ng · h/mL)AUC_(0-1 hour)  604.826 ± 165.795 929.510 ± 193.524 1151.831 ± 214.121103.166 61.783 (ng * h/mL) AUC_(0-2 hours) 1322.703 ± 248.613 1976.926 ±382.453  2621.176 ± 378.846 512.474 ± 292.137 (ng * h/mL) AUC_(0-t)3059.684 ± 985.206 4633.125 ± 1478.184  6621.564 ± 1840.041 7288.003 ±2505.792 (ng · h/mL) AUC_(0-∞)  3476.866 ± 1176.823 5234.806 ± 1423.726 6826.990 ± 1857.487 8074.908 ± 2159.266 (ng · h/mL) ^(a)Median (range)

Example 8 Study on Treatment of Migraine Using the Stable OralComposition

A three-way, double blind, randomized, crossover study was designed tocompare the bioavailability of Example 3 (Celecoxib Oral Solution) atdoses of 120 mg and 240 mg versus placebo and to determine efficacy ofthe stable oral composition in Example 3 in treating migraine. 60subjects with history of 2-6 episodic migraine were recruited into thestudy in 6 sites.

In each study period, a single dose of the stable oral composition wasadministered orally, in the morning, following a 10-hour overnight fast.The administration is done as follows:

-   -   Treatment-1: Composition of Example 3 containing 120 mg of        Celecoxib, administered orally to the volunteers followed by        about 240 ml of water.    -   Treatment-2: Composition of Example 3 containing 240 mg of        Celecoxib, administered orally to the volunteers followed by        about 240 ml of water.    -   Treatment-3: Placebo administered orally to the subjects,        followed by about 240 ml of water.

PK samples were collected at home (if feasible for subjects whoconsented) at 0.5 hr and 2 hr post dosing during actual migraine attack.

Results:

FIG. 4 shows pain free in percentage of human subjects at 2 hoursresults of the Example 3 having 120 mg Celecoxib (Treatment-1) comparedto Vioxx (25 mg, 50 mg) and Cambia (50 mg). FIG. 5 shows pain relief inpercentage of human subjects at 2 hours results of the Example 3 having120 mg Celecoxib (Treatment-1) compared to VIOXX 25 (25 mg), VIOXX 50(50 mg) and CAMBIA 50 (50 mg).

In at least some of the previously described embodiments, one or moreelements used in an embodiment can interchangeably be used in anotherembodiment unless such a replacement is not technically feasible. Itwill be appreciated by those skilled in the art that various otheromissions, additions and modifications may be made to the methods andstructures described above without departing from the scope of theclaimed subject matter. All such modifications and changes are intendedto fall within the scope of the subject matter, as defined by theappended claims.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity.

It will be understood by those within the art that, in general, termsused herein, and especially in the appended claims (e.g., bodies of theappended claims) are generally intended as “open” terms (e.g., the term“including” should be interpreted as “including but not limited to,” theterm “having” should be interpreted as “having at least,” the term“includes” should be interpreted as “includes but is not limited to,”etc.). It will be further understood by those within the art that if aspecific number of an introduced claim recitation is intended, such anintent will be explicitly recited in the claim, and in the absence ofsuch recitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should be interpreted to mean “at least one”or “one or more”); the same holds true for the use of definite articlesused to introduce claim recitations. In addition, even if a specificnumber of an introduced claim recitation is explicitly recited, thoseskilled in the art will recognize that such recitation should beinterpreted to mean at least the recited number (e.g., the barerecitation of “two recitations,” without other modifiers, means at leasttwo recitations, or two or more recitations). Furthermore, in thoseinstances where a convention analogous to “at least one of A, B, and C,etc.” is used, in general such a construction is intended in the senseone having skill in the art would understand the convention (e.g., “asystem having at least one of A, B, and C” would include but not belimited to systems that have A alone, B alone, C alone, A and Btogether, A and C together, B and C together, and/or A, B, and Ctogether, etc.). In those instances where a convention analogous to “atleast one of A, B, or C, etc.” is used, in general such a constructionis intended in the sense one having skill in the art would understandthe convention (e.g., “a system having at least one of A, B, or C” wouldinclude but not be limited to systems that have A alone, B alone, Calone, A and B together, A and C together, B and C together, and/or A,B, and C together, etc.). It will be further understood by those withinthe art that virtually any disjunctive word and/or phrase presenting twoor more alternative terms, whether in the description, claims, ordrawings, should be understood to contemplate the possibilities ofincluding one of the terms, either of the terms, or both terms. Forexample, the phrase “A or B” will be understood to include thepossibilities of “A” or “B” or “A and B.”

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one of skill in the art, for any and allpurposes, such as in terms of providing a written description, allranges disclosed herein also encompass any and all possible sub-rangesand combinations of sub-ranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the likeinclude the number recited and refer to ranges which can be subsequentlybroken down into sub-ranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember. Thus, for example, a group having 1-3 articles refers to groupshaving 1, 2, or 3 articles. Similarly, a group having 1-5 articlesrefers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

What is claimed is:
 1. A stable oral liquid pharmaceutical composition,comprising a therapeutically effective amount of celecoxib, at least onesolubilizer, at least one medium chain glyceride, at least one polarsolvent, and at least one pharmaceutically acceptable excipient, whereinsaid solubilizer is present in an amount from about 35% w/w to about 45%w/w, and wherein said composition does not show any precipitation inFasted-State Simulated Gastric Fluid (FaSSGF) at pH of 2.0, temperatureof 37° C.±0.5° C. and under stirring at a speed of 50 rpm, when measuredat 60 min.
 2. The stable oral liquid pharmaceutical composition of claim1, wherein the composition is essentially free of precipitationinhibitors selected from the group consisting of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer,polyoxyethylene-polyoxypropylene block copolymers, pluronics,polyvinylpyrrolidone, and cellulosic polymers, including hydroxypropylcellulose and hydroxypropyl methylcellulose.
 3. The stable oral liquidpharmaceutical composition of claim 1, wherein the at least onesolubilizer is polyethoxylated castor oil, lauryl macrogolglyceride, ora combination thereof.
 4. The stable oral liquid pharmaceuticalcomposition of claim 1, wherein the at least one medium chain glycerideis glyceryl tricaprylate/tricaprate, glyceryl monocaprylate, or acombination thereof.
 5. The stable oral liquid pharmaceuticalcomposition of claim 1, wherein the at least one polar solvent isselected from the group consisting of propylene glycol, polyethyleneglycols having a molecular weight between 400 and 1000, glycerin, C2 toC8 mono- and poly-alcohols, C7 to C18 alcohols of linear or branchedconfiguration, water and mixtures thereof.
 6. The stable oral liquidpharmaceutical composition of claim 1, wherein the therapeuticallyeffective amount of celecoxib comprises from about 1% to about 80%celecoxib by weight, based on the total weight of the composition. 7.The stable oral liquid pharmaceutical composition of claim 1, wherein aweight ratio of the at least one solubilizer to celecoxib varies fromabout 4.0:1.0 to about 20:1.0.
 8. The stable oral liquid pharmaceuticalcomposition of claim 1, wherein the at least one polar solvent ispresent in an amount of from about 20% to about 80% by weight, based onthe total weight of the composition.
 9. The stable oral liquidpharmaceutical composition of claim 1, wherein a weight ratio of the atleast one solubilizer to the at least one polar solvent varies fromabout 0.60:1.00 to about 1.8:1.00.
 10. The stable oral liquidpharmaceutical composition of claim 1, wherein the at least one mediumchain glyceride is present in an amount of from about 5% to about 75% byweight, based on the total weight of the composition.
 11. The stableoral liquid pharmaceutical composition of claim 1, wherein thecomposition has a mean oil droplet size of not more than 500 nm, whentested in 250 ml of Fasted-State Simulated Gastric Fluid (FaSSGF) at pHof 2.0, temperature of 37° C.±0.5° C. and under stirring at a speed of50 rpm.
 12. The stable oral liquid pharmaceutical composition of claim1, wherein the composition has a viscosity of from about 20 cps to about1000 cps.
 13. The stable oral liquid pharmaceutical composition of claim1, wherein the composition has a density of from about 0.8 gm/cm³ toabout 2 gm/cm³.
 14. The stable oral liquid pharmaceutical composition ofclaim 1, wherein the composition has a transmittance of at least 40%.15. The stable oral liquid pharmaceutical composition of claim 1,wherein the composition has a pH of from about 3 to about
 7. 16. Thestable oral liquid pharmaceutical composition of claim 1, wherein thetherapeutically effect amount of celecoxib is at least about 40% lessthan conventional celecoxib in 400 mg oral capsules.
 17. The stable oralliquid pharmaceutical composition of claim 16, wherein thetherapeutically effect amount of celecoxib is about 240 mg.
 18. Thestable oral liquid pharmaceutical composition of claim 1, wherein thetherapeutically effect amount of celecoxib is at least about 55% lessthan conventional celecoxib in 400 mg oral capsules.
 19. The stable oralliquid pharmaceutical composition of claim 18, wherein thetherapeutically effect amount of celecoxib is about 180 mg.
 20. Thestable oral liquid pharmaceutical composition of claim 1, wherein thetherapeutically effect amount of celecoxib is at least about 70% lessthan conventional celecoxib in 400 mg oral capsules.
 21. The stable oralliquid pharmaceutical composition of claim 20, wherein thetherapeutically effect amount of celecoxib is about 120 mg.
 22. Thestable oral liquid pharmaceutical composition of claim 1, which uponoral administration to a human subject under fasting conditions,provides at least one of the following pharmacokinetic parameters:AUC_((0-15min)) from about 10 ng·h/mL to about 80 ng·h/mL;AUC_((0-30min)) from about 80 ng·h/mL to about 400 ng·h/mL;AUC_((0-1hr)) from about 400 ng·h/mL to about 1500 ng·h/mL;AUC_((0-2hr)) from about 1000 ng·h/mL to about 4000 ng·h/mL; AUC_((0-t))of at least about 2000 ng·h/mL; AUC_((0-∞)) of at least about 2000ng·h/mL; and T_(lag) of not more than 8 minutes.
 23. The stable oralliquid pharmaceutical composition of claim 1, wherein the compositioncomprises: a) a therapeutically effective amount of celecoxib; b) atleast one pharmaceutically acceptable excipient; c) at least onesolubilizer in an amount from about 35% w/w to about 45% w/w; and d) atleast one polar solvent in an amount from about 25% w/w to about 42%w/w, wherein the solubilizer and polar solvent are present in a ratio offrom about 0.60:1 to about 1.8:1; and wherein the stable oral liquidpharmaceutical composition has a viscosity of from about 20 cps to about1000 cps, and a density of from about 0.8 gm/cm³ to about 2 gm/cm³. 24.A stable oral liquid pharmaceutical composition, comprising from about100 mg to 250 mg of celecoxib, at least one pharmaceutically acceptableexcipient, at least one solubilizer, at least one medium chainglyceride, and at least one polar solvent, wherein said solubilizer ispresent in an amount from about 35% w/w to about 45% w/w, and whereinthe composition: a) releases no less than about 70% of the celecoxib ata period of 10 minutes; or b) releases no less than about 80% of thecelecoxib at a period of 15 minutes, in 900 ml of 0.01N HCl with 0.5%sodium lauryl sulfate, when tested in a USP Type 2 apparatus withsinkers at 50 rpm and 37° C.
 25. A method of treating pain in a humansubject, the method comprising administering to the subject a stableoral liquid pharmaceutical composition, comprising a therapeuticallyeffective amount of celecoxib, at least one solubilizer in amount fromabout 35% w/w to about 45% w/w, at least one polar solvent in amountfrom about 25% w/w to about 42% w/w, at least one medium chainglyceride, and at least one pharmaceutically acceptable excipient,wherein the stable oral liquid pharmaceutical composition is essentiallyfree of precipitation inhibitors.
 26. The method of claim 25, whereinthe pain is associated with migraine.
 27. The method of claim 26,wherein the therapeutically effective amount of celecoxib is sufficientto render the subject pain free within 2 hours of administering thestable oral liquid pharmaceutical composition.
 28. A stable oralpharmaceutical composition of celecoxib comprising i. therapeuticallyeffective amount of celecoxib, at least one solubilizer, at least onemedium chain glyceride; and ii. polar solvent comprising mixture ofethanol and glycerin; wherein the composition falls within the shadedregion of a phase diagram, as shown in FIG. 1, wherein boundaries of astable composition are defined by shaded region or the region betweenthe connecting lines between the six points (a, b, c, d, e and f),wherein the composition comprises about 1% to about 80% w/w celecoxiband correspond to a weight % ratio of base composition:ethanol:glycerinof 0.200:0.024:0.712 for a, 0.200:0.376:0.360 for b, 0.200:0.400:0.336for c, 0.536:0.400:0.000 for d, 0.900:0.036:0.00 for e and0.900:0.00:0.036 for f.
 29. The stable oral pharmaceutical compositionof claim 28, wherein said therapeutically effective amount of celecoxibis at least 40% less compared to conventional celecoxib in 400 mg oralcapsules.